CN104109127B - Kinase inhibitor and the method for treating related disease - Google Patents

Abstract

This specification describes the molecular structure of (aminophenylamino)pyrimidinyl benzamide compounds, their synthesis method, and the method of using the compound to inhibit kinases and the treatment of diseases related to B cells.

Description

Kinase inhibitors and methods of treating related diseases

technical field

This specification describes the molecular structure of (aminophenylamino)pyrimidinyl benzamide compounds, their synthesis method, and the method of using the compound to inhibit kinases and the treatment of diseases related to B cells.

Background technique

The mechanism of action of kinases is to transfer a phosphate group from a high-energy donor molecule (such as ATP) to a specific molecule, a process called phosphorylation. Protein kinases alter the activity of specific proteins through phosphorylation, thereby controlling and regulating protein-related signal transduction and other effects on cells. Due to the important role of protein kinases in cell signal transduction, the use of small molecule compounds for specific kinases is helpful for in-depth understanding of cell signal transduction processes. At the same time, small molecular compounds control the function of cells by regulating the activity of kinases, making protein kinases a good drug target in the treatment of clinical diseases.

Bruton's tyrosine kinase (Btk) is a member of the Tec family of non-receptor tyrosine kinases. Btk plays a key role in information transduction in hematopoietic cells (except T lymphocytes and protoplasm cells), especially B cells that play an important role in the pathogenesis of autoimmune and inflammatory diseases. Btk has shown good clinical curative effect on many major difficult diseases, such as rheumatoid arthritis, lymphoma, and leukemia.

Btk plays a key role in the development, differentiation, reproduction, activation and survival of B cells. The effect of Btk on B cells is realized by controlling the B cell receptor (B-cell receptor, BCR) signal transduction pathway. Btk is located immediately downstream of BCR. Under the stimulation of BCR, Btk transmits the signal to the downstream, and through a series of signal transduction, it finally leads to intracellular calcium mobilization and activation of protein kinase C. X-Linked Gammaglobulinemia (also known as Bruton Syndrome, XLA) is a rare genetic disorder. These XLA patients are unable to produce mature B cells. Normal B cells fight off external infections by making antibodies (called immunoglobulins). Because of a lack of B cells and antibodies, people with XLA are prone to serious and even fatal infections. Further research found that the direct cause of the blockage of B cell development was the mutation of the Btk gene. Thus it was confirmed that Btk played an extremely important role in the development and function of normal B cells.

Btk has emerged as an attractive drug target in B-cell-associated cancers, especially B-cell lymphomas and leukemias.

Cells need signals from the BCR to grow and reproduce. Because Btk is an indispensable main member in the BCR signaling pathway. Btk inhibitors block BCR signaling and induce apoptosis in cancer cells. Currently, there are two Btk inhibitors entering clinical treatment of chronic lymphocytic leukemia (Cll) and small lymphocytic lymphoma (Sll) in the United States: ibrutinib (clinical phase III) and AVL-292 (clinical phase II). Expect). (See SE Herman et al. (2011), Blood 117(23):6287-96). Btk has also been associated with acute lymphoblastic leukemia. Acute lymphoblastic leukemia is the most common cancer in children and has a poor prognosis in adults. Genetic analysis found defects in BTK expression in all types of leukemia. Defective Btk protects leukemia cells from apoptosis.

Btk is also a target for the treatment of autoimmune diseases. Rheumatoid arthritis is a chronic autoimmune disease. Btk is an important component of BCR signaling in B cells and FC-γ signaling in myeloid cells. Btk inhibitors are expected to reduce two major components of autoimmune disease: pathogenic autoantibodies produced by B cells and proinflammatory cytokines produced by myeloid cells. In cell experiments, it was confirmed that Btk inhibitors can effectively reduce autoantibodies and pro-inflammatory cytokines. In mice with collagen-induced arthritis, Btk inhibitors reduced autoantibody levels and effectively controlled the disease. These results shed new light on the function of Btk in B-cell or myeloid-driven disease processes and provide a compelling rationale for targeting Btk in rheumatoid arthritis. (see Pan, Zhengying, et al. "Discovery of selective irreversible inhibitors for Bruton's tyrosinekinase." ChemMedChem2.1 (2007): 58-61; Honigberg, Lee A., et al. "The Brutontyrosine kinase inhibitor PCI-32765blocks B-cell Activation and isefficacious in models of autoimmune disease and B-cell malignancy. "Proceedings of the National Academy of Sciences 107.29 (2010): 13075-13080; DiPaolo, Julie A., et al. "Specific Btk inhibition suppresses B cell-and myeloid cell-mediated arthritis. "Nature Chemical Biology 7.1 (2010): 41 _- 50.)

The role of Btk in inflammatory diseases has been demonstrated in the rat basophilic autoimmune leukemia cell (RBL-2H3) model. RBL-2H3 is a common model for studying mast cell inflammatory diseases. Mast cells are rich in basophilic granules and play a dominant role in immunoglobulin E (IgE)-mediated allergic responses. Small interfering RNA (siRNA) and LFM-A13 (an effective Btk inhibitor) can reduce the inflammatory response induced by mast cells by reducing the activity of Btk: RBL treated with siRNA and LFM-A13 - In 2H3 mast cells, the release of the pro-inflammatory mediator histamine was reduced by 20-25%.

It has also been reported in the literature that Btk serves as a therapeutic target in heteroimmune diseases and thromboembolic diseases.

Therefore, the object of the present invention is to provide a new class of compounds for the treatment of autoimmune diseases, heteroimmune diseases, inflammatory diseases, cancer, or thromboembolic diseases.

Contents of the invention

In one aspect of the present invention, there is provided a compound of formula (IA), or its pharmaceutically active metabolite, pharmaceutically acceptable solvate, pharmaceutically acceptable salt, pharmaceutically acceptable ester, or a pharmaceutically acceptable prodrug, or a tautomeric form thereof, or an isotopically substituted form thereof (including, but not limited to, for example, ² H in place of ¹ H, and ¹⁸ F in place of ¹⁹ F):

in,

R ₁ and R ₂ are independently of each other, identically or differently, selected from: hydrogen (when L ₁ or L ₂ does not exist), -C(O)-, -C(S)-, -C(O) O-, -OC(O)-, -N(R ^d )C(O)-, -C(O)N(R ^d )-, -S(O)-, -S(O) ₂ -, - S(O) ₂ N(R ^d )-, -N(R ^d )S(O) ₂ -, or -C(=NR ^d )-;

L ¹ and L ² are independently of each other, identically or differently, selected from:

does not exist;

hydrogen;

C _2-10 alkenyl, C _2-10 alkenyl substituted by C _1-6 alkyl, -C _1-3 alkyl-NHC(O)-C _2-10 alkenyl, -C _1-3 alkyl -C(O)-C _2-10 alkenyl, -C _1-3 alkyl-C(S)-C _2-10 alkenyl, -C _1-3 alkyl-C(O)OC _2-10 alkenyl Base, -C _1-3 alkyl-OC(O)-C _2-10 alkenyl, -C _1-3 alkyl-NHC(O)-C _2-10 alkenyl, -C _1-3 alkyl- C(O)NH-C _2-10 alkenyl, -C _1-3 alkyl-S(O)-C _2-10 alkenyl, -C _1-3 alkyl-S(O) ₂ -C _{2- 10} alkenyl, -C _1-3 alkyl-S (O) ₂ NH-C _2-10 alkenyl, -C _1-3 alkyl-NHS (O) ₂ -C _2-10 alkenyl, or -C _1-3 alkyl-C(=NH)-C _2-10 alkenyl, the above-mentioned C _2-10 alkenyl can optionally be independently selected from halogen, R ^a O- and R at the position that can be substituted ^b R ^c N- substituents are substituted one or more times, the above-mentioned C _1-3 alkyl and C _1-6 alkyl are independently optionally 1 or 2 independently selected from alkyl, alkenyl, alkyne radical, halogen, -NO ₂ , -CN, haloalkyl, -OR ^a , -OC(O)R ^a , -NR ^a R ^b , -N(R ^b )C(O)R ^a , -N(R ^b )S(O) ₂ R ^a , -SR ^a , -S(O)R ^c , -S(O) ₂ R ^c , -S(O) ₂ NR ^a R ^b , -C(O)R ^a , - C(O)OR ^a , -C(O)NR ^a R ^b , -(C _1-6 alkylene)-NO ₂ , -(C _1-6 alkylene)-CN, -(C _1-6 Alkylene)-OR ^a ,-(C _1-6 alkylene)-OC(O)R ^a ,-(C _1-6 alkylene)-NR ^a R ^b ,-(C _1-6 alkylene Base)-N(R ^b )C(O)R ^a ,-(C _1-6 alkylene)-N(R ^b )S(O) ₂ R ^a ,-(C _1-6 alkylene)- SR ^a ,-(C _1-6 alkylene)-S(O)R ^c ,-(C _1-6 alkylene)-S(O) ₂ R ^c ,-(C _1-6 alkylene) -S(O) ₂ NR ^a R ^b , -(C _1-6 alkylene)-C(O)R ^a , -(C _1-6 alkylene)-C(O)OR ^a , or -( C _1-6 alkylene)-C (O) NR ^a R ^b group substitution; or

C _2-10 alkynyl, C _2-10 alkynyl substituted by C _1-6 alkyl, -C _1-3 alkyl-NHC(O)-C _2-10 alkynyl, -C _1-3 alkyl -C(O)-C _2-10 alkynyl, -C _1-3 alkyl-C(S)-C _2-10 alkynyl, -C _1-3 alkyl-C(O)OC _2-10 alkyne Base, -C _1-3 alkyl-OC (O)-C _2-10 alkynyl, -C _1-3 alkyl-NHC (O)-C _2-10 alkynyl, -C _1-3 alkyl- C(O)NH-C _2-10 alkynyl, -C _1-3 alkyl-S(O)-C _2-10 alkynyl, -C _1-3 alkyl-S(O) ₂ -C _{2- 10} alkynyl, -C _1-3 alkyl-S (O) ₂ NH-C _2-10 alkynyl, -C _1-3 alkyl-NHS (O) ₂ -C _2-10 alkynyl, or -C _1-3 alkyl-C(=NH)-C _2-10 alkynyl, the above-mentioned C _2-10 alkynyl can optionally be independently selected from halogen, R ^a O- and R at the position that can be substituted ^b R ^c N- substituents are substituted one or more times, the above-mentioned C _1-3 alkyl and C _1-6 alkyl are independently optionally 1 or 2 independently selected from alkyl, alkenyl, alkyne radical, halogen, -NO ₂ , -CN, haloalkyl, -OR ^a , -OC(O)R ^a , -NR ^a R ^b , -N(R ^b )C(O)R ^a , -N(R ^b )S(O) ₂ R ^a , -SR ^a , -S(O)R ^c , -S(O) ₂ R ^c , -S(O) ₂ NR ^a R ^b , -C(O)R ^a , - C(O)OR ^a , -C(O)NR ^a R ^b , -(C _1-6 alkylene)-NO ₂ , -(C _1-6 alkylene)-CN, -(C _1-6 Alkylene)-OR ^a ,-(C _1-6 alkylene)-OC(O)R ^a ,-(C _1-6 alkylene)-NR ^a R ^b ,-(C _1-6 alkylene Base)-N(R ^b )C(O)R ^a ,-(C _1-6 alkylene)-N(R ^b )S(O) ₂ R ^a ,-(C _1-6 alkylene)- SR ^a ,-(C _1-6 alkylene)-S(O)R ^c ,-(C _1-6 alkylene)-S(O) ₂ R ^c ,-(C _1-6 alkylene) -S(O) ₂ NR ^a R ^b , -(C _1-6 alkylene)-C(O)R ^a , -(C _1-6 alkylene)-C(O)OR ^a , or -( C _1-6 alkylene)-C (O) NR ^a R ^b group substitution;

R ₃ is selected from: hydrogen, alkyl, alkenyl, alkynyl, -(C _1-6 alkylene)-NO ₂ , -(C _1-6 alkylene)-CN, -(C _1-6 alkylene Alkyl)-OR ^a ,-(C _1-6 alkylene)-OC(O)R ^a ,-(C _1-6 alkylene)-NR ^a R ^b ,-(C _1-6 alkylene )-N(R ^b )C(O)R ^a ,-(C _1-6 alkylene)-N(R ^b )S(O) ₂ R ^a ,-(C _1-6 alkylene)-SR ^a ，-(C _1-6 alkylene)-S(O)R ^c ，-(C _1-6 alkylene)-S(O) ₂ R ^c ，-(C _1-6 alkylene)- S(O) ₂ NR ^a R ^b , -(C _1-6 alkylene)-C(O)R ^a , -(C _1-6 alkylene)-C(O)OR ^a , or -(C _1-6 alkylene)-C(O)NR ^a R ^b ;

R ₄ is selected from: hydrogen, alkyl, alkenyl, alkynyl, -(C _1-6 alkylene)-NO ₂ , -(C _1-6 alkylene)-CN, -(C _1-6 alkylene Alkyl)-OR ^a ,-(C _1-6 alkylene)-OC(O)R ^a ,-(C _1-6 alkylene)-NR ^a R ^b ,-(C _1-6 alkylene )-N(R ^b )C(O)R ^a ,-(C _1-6 alkylene)-N(R ^b )S(O) ₂ R ^a ,-(C _1-6 alkylene)-SR ^a ，-(C _1-6 alkylene)-S(O)R ^c ，-(C _1-6 alkylene)-S(O) ₂ R ^c ，-(C _1-6 alkylene)- S(O) ₂ NR ^a R ^b , -(C _1-6 alkylene)-C(O)R ^a , -(C _1-6 alkylene)-C(O)OR ^a , or -(C _1-6 alkylene)-C(O)NR ^a R ^b ;

Z ₁ at each occurrence is independently selected from: alkyl, alkenyl, alkynyl, halogen, -NO ₂ , -CN, haloalkyl, -OR ^a , -OC(O)R ^a , -NR ^a R ^b , -N(R ^b )C(O)R ^a , -N(R ^b )S(O) ₂ R ^a , -SR ^a , -S(O)R ^c , -S(O) ₂ R ^c , -S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -(C _1-6 alkylene)-NO ₂ ,-(C _1-6 alkylene)-CN,-(C _1-6 alkylene)-OR ^a ,-(C _1-6 alkylene)-OC(O)R ^a ,-(C _{1 -6} alkylene)-NR ^a R ^b , -(C _1-6 alkylene)-N(R ^b )C(O)R ^a ,-(C _1-6 alkylene)-N(R ^b )S(O) ₂ R ^a ,-(C _1-6 alkylene)-SR ^a ,-(C _1-6 alkylene)-S(O)R ^c ,-(C _1-6 alkylene )-S(O) ₂ R ^c ,-(C _1-6 alkylene)-S(O) ₂ NR ^a R ^b ,-(C _1-6 alkylene)-C(O)R ^a ,- (C _1-6 alkylene)-C(O)OR ^a , or -(C _1-6 alkylene)-C(O)NR ^a R ^b ; or

Aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycle, arylalkyl, heteroarylalkyl, cycloalkylalkyl, cycloalkenylalkyl, or heterocycloalkyl; wherein aryl Each of , heteroaryl, cycloalkyl, cycloalkenyl and heterocyclic moieties, as a substituent or part of a substituent, is independently unsubstituted or replaced by 1, 2, 3, 4 or 5 As substituted by a substituent represented by R ^z ;

m1 is 0, 1, 2, 3 or 4,

n is 0, 1, 2, 3 or 4,

The condition is m1+n≤4,

Z ₂ are each independently selected from each occurrence: alkyl, alkenyl, alkynyl, halogen, -NO ₂ , -CN, haloalkyl, -OR ^a , -OC(O)R ^a , -NR ^a R ^b , -N(R ^b )C(O)R ^a , -N(R ^b )S(O) ₂ R ^a , -SR ^a , -S(O)R ^c , -S(O) ₂ R ^c , -S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -(C _1-6 alkylene)-NO ₂ ,-(C _1-6 alkylene)-CN,-(C _1-6 alkylene)-OR ^a ,-(C _1-6 alkylene)-OC(O)R ^a ,-(C _{1 -6} alkylene)-NR ^a R ^b , -(C _1-6 alkylene)-N(R ^b )C(O)R ^a ,-(C _1-6 alkylene)-N(R ^b )S(O) ₂ R ^a ,-(C _1-6 alkylene)-SR ^a ,-(C _1-6 alkylene)-S(O)R ^c ,-(C _1-6 alkylene )-S(O) ₂ R ^c ,-(C _1-6 alkylene)-S(O) ₂ NR ^a R ^b ,-(C _1-6 alkylene)-C(O)R ^a ,- (C _1-6 alkylene)-C(O)OR ^a , or -(C _1-6 alkylene)-C(O)NR ^a R ^b ;

m2 is 0, 1 or 2,

Z ₃ are each independently selected from each occurrence of: alkyl, alkenyl, alkynyl, halogen, -NO ₂ , -CN, haloalkyl, -OR ^a , -OC(O)R ^a , -NR ^a R ^b , -N(R ^b )C(O)R ^a , -N(R ^b )S(O) ₂ R ^a , -SR ^a , -S(O)R ^c , -S(O) ₂ R ^c , -S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -(C _1-6 alkylene)-NO ₂ ,-(C _1-6 alkylene)-CN,-(C _1-6 alkylene)-OR ^a ,-(C _1-6 alkylene)-OC(O)R ^a ,-(C _{1 -6} alkylene)-NR ^a R ^b , -(C _1-6 alkylene)-N(R ^b )C(O)R ^a ,-(C _1-6 alkylene)-N(R ^b )S(O) ₂ R ^a ,-(C _1-6 alkylene)-SR ^a ,-(C _1-6 alkylene)-S(O)R ^c ,-(C _1-6 alkylene )-S(O) ₂ R ^c ,-(C _1-6 alkylene)-S(O) ₂ NR ^a R ^b ,-(C _1-6 alkylene)-C(O)R ^a ,- (C _1-6 alkylene)-C(O)OR ^a , or -(C _1-6 alkylene)-C(O)NR ^a R ^b ; or

Aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycle, arylalkyl, heteroarylalkyl, cycloalkylalkyl, cycloalkenylalkyl, or heterocycloalkyl; wherein aryl Each of , heteroaryl, cycloalkyl, cycloalkenyl and heterocyclic moieties, as a substituent or part of a substituent, is independently unsubstituted or replaced by 1, 2, 3, 4 or 5 As substituted by a substituent represented by R ^z ;

m3 is 0, 1, 2, 3, 4 or 5,

R ^d each occurrence is independently selected from: hydrogen or alkyl, which is optionally selected from 1 or 2 independently selected from -OH, -O(alkyl), halogen, -C(O)(alkyl ), -C(O)O(alkyl), -C(O)NH ₂ , -C(O)N(H)(alkyl), -C(O)N(alkyl) ₂ , cycloalkyl , cycloalkenyl, heterocycle, aryl, and heteroaryl substituents;

R ^z is independently selected from each occurrence of each other: alkyl, alkenyl, alkynyl, halogen, -NO ₂ , -CN, haloalkyl, -OR ^a , -OC(O)R ^a , -NR ^a R ^b , -N(R ^b )C(O)R ^a , -N(R ^b )S(O) ₂ R ^a , -SR ^a , -S(O)R ^c , -S(O) ₂ R ^c , -S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -(C _1-6 alkylene)-NO ₂ ,-(C _1-6 alkylene)-CN,-(C _1-6 alkylene)-OR ^a ,-(C _1-6 alkylene)-OC(O)R ^a ,-(C _{1 -6} alkylene)-NR ^a R ^b , -(C _1-6 alkylene)-N(R ^b )C(O)R ^a ,-(C _1-6 alkylene)-N(R ^b )S(O) ₂ R ^a ,-(C _1-6 alkylene)-SR ^a ,-(C _1-6 alkylene)-S(O)R ^c ,-(C _1-6 alkylene )-S(O) ₂ R ^c ,-(C _1-6 alkylene)-S(O) ₂ NR ^a R ^b ,-(C _1-6 alkylene)-C(O)R ^a ,- (C _1-6 alkylene)-C(O)OR ^a , or -(C _1-6 alkylene)-C(O)NR ^a R ^b ;

Each ^occurrence of R is independently selected from: hydrogen, alkyl, or haloalkyl;

Each occurrence of R ^b is independently selected from: hydrogen, alkyl, or haloalkyl;

Each occurrence of R ^c is independently selected from: hydrogen, alkyl, or haloalkyl.

In a preferred embodiment, the compound of formula (I-A) is a compound of formula (I-B) or formula (I-C):

wherein R ₁ , R ₂ , R ₃ , R ₄ , L ₁ , L ₂ , Z ₁ , Z ₂ , Z ₃ , m1 , m2, and m3 are as defined in claim 1 .

In another preferred embodiment, n=0.

In another preferred embodiment, R ₁ and R ₂ are independently of each other, identical or different, selected from: hydrogen (when L ₁ or L ₂ does not exist), -C(O)-, -C (S)-, -C(O)O-, -OC(O)-, -NHC(O)-, -C(O)NH-, -S(O)-, -S(O) _2- , -S(O) ₂ NH-, -NHS(O) ₂ -, or -C(=NH)-.

^In another preferred embodiment, L and ^L are independently, identically or differently, selected from:

does not exist;

hydrogen; or

C _2-10 alkenyl, C _2-10 alkenyl substituted by C _1-6 alkyl, -C _1-3 alkyl-NHC(O)-C _2-10 alkenyl, -C _1-3 alkyl -C(O)-C _2-10 alkenyl, -C _1-3 alkyl-C(S)-C _2-10 alkenyl, -C _1-3 alkyl-C(O)OC _2-10 alkenyl Base, -C _1-3 alkyl-OC(O)-C _2-10 alkenyl, -C _1-3 alkyl-NHC(O)-C _2-10 alkenyl, -C _1-3 alkyl- C(O)NH-C _2-10 alkenyl, -C _1-3 alkyl-S(O)-C _2-10 alkenyl, -C _1-3 alkyl-S(O) ₂ -C _{2- 10} alkenyl, -C _1-3 alkyl-S (O) ₂ NH-C _2-10 alkenyl, -C _1-3 alkyl-NHS (O) ₂ -C _2-10 alkenyl, or -C _1-3 alkyl-C(=NH)-C _2-10 alkenyl, the above-mentioned C _2-10 alkenyl can optionally be independently selected from halogen, R ^a O- and R at the position that can be substituted ^b R ^c N- substituents are substituted one or more times; the above-mentioned C _1-3 alkyl and C _1-6 alkyl are independently optionally selected from 1 or 2 independently selected from alkyl, alkenyl, alkyne radical, halogen, -NO ₂ , -CN, haloalkyl, -OR ^a , -OC(O)R ^a , -NR ^a R ^b , -N(R ^b )C(O)R ^a , -N(R ^b )S(O) ₂ R ^a , -SR ^a , -S(O)R ^c , -S(O) ₂ R ^c , -S(O) ₂ NR ^a R ^b , -C(O)R ^a , - C(O)OR ^a , -C(O)NR ^a R ^b , -(C _1-6 alkylene)-NO ₂ , -(C _1-6 alkylene)-CN, -(C _1-6 Alkylene)-OR ^a ,-(C _1-6 alkylene)-OC(O)R ^a ,-(C _1-6 alkylene)-NR ^a R ^b ,-(C _1-6 alkylene Base)-N(R ^b )C(O)R ^a ,-(C _1-6 alkylene)-N(R ^b )S(O) ₂ R ^a ,-(C _1-6 alkylene)- SR ^a ,-(C _1-6 alkylene)-S(O)R ^c ,-(C _1-6 alkylene)-S(O) ₂ R ^c ,-(C _1-6 alkylene) -S(O) ₂ NR ^a R ^b , -(C _1-6 alkylene)-C(O)R ^a , -(C _1-6 alkylene)-C(O)OR ^a , or -( C _1-6 alkylene) -C (O) NR ^a R ^b group substitution.

In another preferred embodiment, R ₃ is selected from: hydrogen, or -C _1-10 alkyl, -C _2-10 alkenyl, -C _2-10 alkynyl.

In another preferred embodiment, R ₄ is selected from: hydrogen, or -C _1-10 alkyl, -C _2-10 alkenyl, -C _2-10 alkynyl.

In another preferred embodiment, Z ₁ , Z ₂ and Z ₃ are each independently selected from each occurrence of:

-C _1-10 alkyl, -C _2-10 alkenyl, -C _2-10 alkynyl, halogen, -NO ₂ , -CN, halogenated C _1-10 alkyl, -OR ^a , -OC(O )R ^a ,-NR ^a R ^a ,-N(R ^b )C(O)R ^a ,-N(R ^b )S(O) ₂ R ^a ,-SR ^a ,-S(O)R ^c ,- S(O) ₂ R ^c , -S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -(C _{1- 6} alkylene)-NO ₂ ,-(C _1-6 alkylene)-CN,-(C _1-6 alkylene)-OR ^a ,-(C _1-6 alkylene)-OC(O )R ^a ,-(C _1-6 alkylene)-NR ^a R ^b ,-(C _1-6 alkylene)-N(R ^b )C(O)R ^a ,-(C _1-6 alkylene Alkyl)-N(R ^b )S(O) ₂ R ^a ,-(C _1-6 alkylene)-SR ^a ,-(C _1-6 alkylene)-S(O)R ^c ,- (C _1-6 alkylene)-S(O) ₂ R ^c , -(C _1-6 alkylene)-S(O) ₂ NR ^a R ^b ,-(C _1-6 alkylene)- C(O)R ^a , -(C _1-6 alkylene)-C(O)OR ^a , or -(C _1-6 alkylene)-C(O)NR ^a R ^b ; or phenyl, 5 or 6 membered heteroaryl, C _3-8 cycloalkyl, heterocycle, benzyl, C _3-8 cycloalkyl C _1-10 alkyl, or heterocycle-C _1-10 alkyl.

In another preferred embodiment, m1, m2 and m3 are 0, 1 or 2 independently of each other.

In another preferred embodiment ^Rd is hydrogen.

In another preferred embodiment, each ^occurrence of R is independently selected from: hydrogen or C _1-10 alkyl.

In another preferred embodiment, each occurrence of R ^b is independently selected from: hydrogen or C _1-10 alkyl.

In another preferred embodiment, each occurrence of R ^c is independently selected from: hydrogen or C _1-10 alkyl.

In another aspect of the invention, there is provided

A compound of formula (I), or a pharmaceutically acceptable salt thereof:

in,

W is selected from H, C _1-6 alkyl (the above C _1-6 alkyl is optionally selected from 1 or 2 independently selected from alkyl, alkenyl, alkynyl, halogen, -NO ₂ , -CN, haloalkane base, -OR ^a , -OC(O)R ^a , -NR ^a R ^b , -N(R ^b )C(O)R ^a , -N(R ^b )S(O) ₂ R ^a , -SR ^a , -S(O)R ^c , -S(O) ₂ R ^c , -S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a , -C(O) NR ^a R ^b , -(C _1-6 alkylene) -NO ₂ , -(C _1-6 alkylene) -CN, -(C _1-6 alkylene) -OR ^a , -(C _{1 -6} alkylene)-OC(O)R ^a ,-(C _1-6 alkylene)-NR ^a R ^b ,-(C _1-6 alkylene)-N(R ^b )C(O) R ^a ,-(C _1-6 alkylene)-N(R ^b )S(O) ₂ R ^a ,-(C _1-6 alkylene)-SR ^a ,-(C _1-6 alkylene )-S(O)R ^c ,-(C _1-6 alkylene)-S(O) ₂ R ^c ,-(C _1-6 alkylene)-S(O) ₂ NR ^a R ^b ,- (C _1-6 alkylene)-C(O)R ^a , -(C _1-6 alkylene)-C(O)OR ^a , or -(C _1-6 alkylene)-C(O ) group substitution of NR ^a R ^b ; R ^a at each occurrence is independently selected from: hydrogen or C _1-10 alkyl; R ^b at each occurrence is independently selected from: hydrogen or C _{1- 10} alkyl; each occurrence of R ^c is independently selected from each other: hydrogen or C _1-10 alkyl), -(NH-CO) _n -LL ₃ , -(CO-NH) _n -LL ₃ , and -(NH-CO) _n -NH-LL ₃ ,

in

L is a bond, C _1-3 alkylene, or C _2-3 alkenylene,

L ₃ is C _3-8 cycloalkyl such as

Aryl groups such as phenyl, naphthyl, phenanthrenyl, anthracenyl, fluorenyl and indenyl, or heteroaryl groups such as

The C _3-8 cycloalkyl, aryl and heteroaryl are optionally substituted by 1, 2 or 3 substituents selected from the group consisting of: halogen such as F and Cl, amino, C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkyl such as perhalogenated C _1-6 alkyl such as CF ₃ (the aforementioned C _1-6 alkyl, C _1-6 alkoxy, halogenated C ₁ The C _1-6 alkyl in _-6 alkyl is optionally selected from 1 or 2 independently selected from alkyl, alkenyl, alkynyl, halogen, -NO ₂ , -CN, haloalkyl, -OR ^a , -OC (O)R ^a , -NR ^a R ^b , -N(R ^b )C(O)R ^a , -N(R ^b )S(O) ₂ R ^a , -SR ^a , -S(O)R ^c , -S(O) ₂ R ^c , -S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -(C _1-6 alkylene)-NO ₂ ,-(C _1-6 alkylene)-CN,-(C _1-6 alkylene)-OR ^a ,-(C _1-6 alkylene)-OC (O)R ^a ,-(C _1-6 alkylene)-NR ^a R ^b ,-(C _1-6 alkylene)-N(R ^b )C(O)R ^a ,-(C _{1- 6} alkylene)-N(R ^b )S(O) ₂ R ^a , -(C _1-6 alkylene)-SR ^a ,-(C _1-6 alkylene)-S(O)R ^c ,-(C _1-6 alkylene)-S(O) ₂ R ^c ,-(C _1-6 alkylene)-S(O) ₂ NR ^a R ^b ,-(C _1-6 alkylene )-C(O)R ^a , -(C _1-6 alkylene)-C(O)OR ^a , or -(C _1-6 alkylene)-C(O)NR ^a R ^b group Substitution; R ^a is independently selected from each occurrence of: hydrogen or C _1-10 alkyl; R ^b is independently selected from each occurrence of: hydrogen or C _1-10 alkyl; R ^c in each The second occurrence is independently selected from: hydrogen or C _1-10 alkyl), n is an integer 0 or 1,

X is selected from H, halogen such as F and Cl, and C _1-6 alkyl such as methyl (the above-mentioned C _1-6 alkyl is optionally selected from 1 or 2 independently selected from alkyl, alkenyl, alkynyl, Halogen, -NO ₂ , -CN, haloalkyl, -OR ^a , -OC(O)R ^a , -NR ^a R ^b , -N(R ^b )C(O)R ^a , -N(R ^b )S (O) ₂ R ^a , -SR ^a , -S(O)R ^c , -S(O) ₂ R ^c , -S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C( O)OR ^a ,-C(O)NR ^a R ^b ,-(C _1-6 alkylene)-NO ₂ ,-(C _1-6 alkylene)-CN,-(C _1-6 alkylene Base)-OR ^a ,-(C _1-6 alkylene)-OC(O)R ^a ,-(C _1-6 alkylene)-NR ^a R ^b ,-(C _1-6 alkylene) -N(R ^b )C(O)R ^a ,-(C _1-6 alkylene)-N(R ^b )S(O) ₂ R ^a ,-(C _1-6 alkylene)-SR ^a ,-(C _1-6 alkylene)-S(O)R ^c ,-(C _1-6 alkylene)-S(O) ₂ R ^c ,-(C _1-6 alkylene)-S (O) ₂ NR ^a R ^b , -(C _1-6 alkylene)-C(O)R ^a , -(C _1-6 alkylene)-C(O)OR ^a , or -(C _{1 -6} alkylene)-C(O)NR ^a group substitution of R ^b ; R ^a at each occurrence is independently selected from each other: hydrogen or C _1-10 alkyl; R ^b at each occurrence of each other independently selected from: hydrogen or ^C _1-10 alkyl; R in each occurrence is independently selected from: hydrogen or C _1-10 alkyl),

R ₁ and R ₂ are independently of each other, identically or differently, selected from H, C(O) and S(O) ₂ ;

L and L are independently _of each other, identically or differently, selected from C _{2-3 alkenyl} optionally substituted by C _1-3 alkyl, and C _1-3 alkyl-NHC(O)-C _2-3 alkenyl, wherein "C _2-3 alkenyl optionally substituted by C _1-3 alkyl" and "C _1-3 alkyl-NHC(O)-C _2-3 alkenyl" The above-mentioned C _1-3 alkyl is optionally selected from 1 or 2 independently selected from alkyl, alkenyl, alkynyl, halogen, -NO ₂ , -CN, haloalkyl, -OR ^a , -OC(O)R ^a , -NR ^a R ^b , -N(R ^b )C(O)R ^a , -N(R ^b )S(O) ₂ R ^a , -SR ^a , -S(O)R ^c , -S( O) ₂ R ^c , -S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -(C _1-6 Alkyl)-NO ₂ ,-(C _1-6 alkylene)-CN,-(C _1-6 alkylene)-OR ^a ,-(C _1-6 alkylene)-OC(O)R ^a ,-(C _1-6 alkylene)-NR ^a R ^b ,-(C _1-6 alkylene)-N(R ^b )C(O)R ^a ,-(C _1-6 alkylene )-N(R ^b )S(O) ₂ R ^a ,-(C _1-6 alkylene)-SR ^a ,-(C _1-6 alkylene)-S(O)R ^c ,-(C _1-6 alkylene)-S(O) ₂ R ^c , -(C _1-6 alkylene)-S(O) ₂ NR ^a R ^b ,-(C _1-6 alkylene)-C( O) R ^a , -(C _1-6 alkylene)-C(O)OR ^a , or -(C _1-6 alkylene)-C(O)NR ^a R ^b group substitution; R ^a independently at each occurrence from: hydrogen or C _1-10 alkyl; R ^b independently at each occurrence from: hydrogen or ^C _1-10 alkyl; R at each occurrence from each other independently selected from: hydrogen or C _1-10 alkyl;

The premise is that when R ₁ is H, L ₁ is absent, and when R ₂ is H, L ₂ is absent.

In a preferred embodiment,

W is selected from H, ethyl, -(NH-CO) _n -LL ₃ , -(CO-NH) _n -LL ₃ , and -(NH-CO) _n -NH-LL ₃ , wherein

L is a bond or a vinylene group,

_L is cyclopropyl, phenyl, naphthyl, isoxazolyl, or benzo[d] optionally substituted by 1 or ₂ substituents selected from F, Cl, amino, methoxy, and CF ][1,3]dioxolyl, n is an integer 1.

In another preferred embodiment,

X is selected from H, F, Cl, and methyl.

In another preferred embodiment,

R ₁ and R ₂ are independently of each other, identically or differently, selected from H, C(O) and S(O) ₂ ;

L ₁ and L ₂ are independently of each other, identically or differently, selected from C _2-3 alkenyl, and methyl-NHC (O)-vinyl;

The premise is that when R ₁ is H, L ₁ is absent, and when R ₂ is H, L ₂ is absent.

In another preferred embodiment,

W is selected from H, ethyl, -(NH-CO) _n -LL ₃ , -(CO-NH) _n -LL ₃ , and -(NH-CO) _n -NH-LL ₃ , wherein

L is a bond or a vinylene group,

_L is cyclopropyl, phenyl, naphthyl, isoxazolyl, or benzo[d] optionally substituted by 1 or ₂ substituents selected from F, Cl, amino, methoxy, and CF ][1,3]dioxolyl, n is an integer 1,

X is selected from H, F, Cl, and methyl,

R ₁ and R ₂ are independently of each other, identically or differently, selected from H, C(O) and S(O) ₂ ;

L ₁ and L ₂ are independently of each other, identically or differently, selected from C _2-3 alkenyl, and methyl-NHC (O)-vinyl;

The premise is that when R ₁ is H, L ₁ is absent, and when R ₂ is H, L ₂ is absent.

In another aspect of the present invention, there is provided a compound selected from:

In another aspect of the present invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention and a pharmaceutically acceptable excipient.

In another aspect of the invention there is provided the use of a compound of the invention in the manufacture of a medicament for the treatment of an autoimmune disease, a heteroimmune disease, an inflammatory disease, cancer, or a thromboembolic disease.

In another aspect of the invention, there is provided a method of treating an autoimmune disease, a heteroimmune disease, an inflammatory disease, cancer, or a thromboembolic disease comprising a compound of the invention or a combination of the invention The compound is administered to a subject in need thereof, for example a mammal such as a human.

In any and all embodiments, substituents may be selected from a subset of the listed alternatives. For example, in some embodiments, W is selected from H, ethyl, -(NH-CO) _n -LL ₃ , -(CO-NH) _n -LL ₃ , and -(NH-CO) _n -NH-LL ₃ . In some further embodiments, W is selected from -(NH-CO) _n -LL ₃ , -(CO-NH) _n -LL ₃ , and -(NH-CO) _n -NH-LL ₃ . In yet further embodiments, W is selected from -(NH-CO) _n -LL ₃ .

In another aspect of the present invention, there is provided a compound of the present invention in the form of a salt, wherein the salt is a salt formed with an acid or a base, wherein the acid includes an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, Metaphosphoric acid; organic acids such as acetic acid, propionic acid, caproic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoro Acetic acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxybenzoic acid Ethylsulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4′- Methylbis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxyl Naphthoic acid, salicylic acid, stearic acid, muconic acid; organic bases such as ethanolamine, diethanolamine, triethanolamine, trimethylamine, N-methylglucamine; and inorganic bases such as aluminum hydroxide, calcium hydroxide, hydroxide Potassium, Sodium Carbonate, Sodium Hydroxide.

In another aspect of the invention, a compound of the invention forms a covalent bond with Cys481 residue of Btk or a cysteine residue at the cognate corresponding position of another tyrosine kinase.

In another aspect of the invention, a compound of the invention forms a covalent bond with an amino acid residue of Btk.

In another aspect of the invention, the compounds of the invention are irreversible inhibitors of Btk.

In another aspect of the invention, when a compound of the invention binds to a kinase, the catalytic domain of the kinase adopts an inactive conformation, such as a DFG-out conformation.

In another aspect of the invention, compounds of the invention are capable of inhibiting phosphorylation of Tyr551 and/or Tyr223 residues of Btk.

In another aspect of the present invention, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention and a pharmaceutically acceptable excipient, said pharmaceutical composition being formulated for a group selected from The route of administration is oral, parenteral, buccal, nasal, topical or rectal.

In another aspect of the invention, the invention provides a method for treating or preventing autoimmune diseases or conditions, heteroimmune diseases or conditions, cancer, mastocytosis, osteoporosis or bone resorption disorders, inflammatory diseases A method comprising administering a therapeutically or prophylactically effective amount of a compound or pharmaceutical composition of the present invention to a patient in need thereof; preferably, the method is a method for treating cancer.

In another aspect of the invention, the invention provides a method for treating or preventing autoimmune diseases or conditions, heteroimmune diseases or conditions, cancer, mastocytosis, osteoporosis or bone resorption disorders, inflammatory diseases method, which includes:

with at least one other pharmaceutical agent for the treatment or prevention of an autoimmune disease or condition, a heteroimmune disease or condition, cancer, mastocytosis, osteoporosis or bone resorption disorders, an inflammatory disease, or

With at least one other medicament for overcoming side effects in the treatment or prevention of an autoimmune disease or condition, a heteroimmune disease or condition, cancer, mastocytosis, osteoporosis or bone resorption disorders, an inflammatory disease reagent,

Administering a therapeutically or prophylactically effective amount of a compound or pharmaceutical composition of the invention to a patient in need;

Preferably, the method is a method of treating cancer and said at least one other pharmaceutical agent is an antibody drug such as anti-CD20 or anti-CD68.

In another aspect of the present invention, the present invention provides: the use of the compound or pharmaceutical composition of the present invention in the preparation of a medicament for the treatment or prevention of the following diseases or conditions: autoimmune diseases or conditions, heteroimmune diseases or conditions, Cancer, mastocytosis, osteoporosis or bone resorption disorders, inflammatory disease.

In another aspect of the present invention, the present invention provides: the use of the compound or pharmaceutical composition of the present invention in combination with an antibody drug such as anti-CD20 or anti-CD68 in the preparation of a drug for treating cancer.

In another aspect of the invention, the invention provides a kit comprising a carrier, package or container, compartmentalized to receive one or more containers, each container comprising a single element, said At least one of the elements is a compound or pharmaceutical composition of the invention, optionally at least one of said elements is for the treatment or prevention of an autoimmune disease or condition, a heteroimmune disease or condition, cancer, mastocytosis, Osteoporosis or bone resorption disorders, at least one other pharmaceutical agent for an inflammatory disease, or for overcoming the effects in the treatment or prevention of an autoimmune disease or condition, a heteroimmune disease or condition, cancer, mastocytosis, bone Osteoporosis or bone resorption disorders, side effects of at least one other pharmaceutical agent during an inflammatory disease process. In a preferred embodiment, the kit is for the treatment of cancer and at least one of said elements is a compound or pharmaceutical composition of the invention. In a preferred embodiment, the kit is used for the treatment of cancer and at least one of the elements is a compound of the present invention or a pharmaceutical composition, and at least another of the elements is an antibody drug such as anti-CD20 and/or or anti-CD68.

Other objects, features and advantages of the methods and compositions described herein will be apparent from the detailed description below. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments, are given by way of illustration only, since it is from this detailed description that various aspects of this disclosure will be discussed. Variations and modifications within the spirit and scope of the invention will become apparent to those skilled in the art. The section headings used herein are for organizational purposes only and are not to be construed as limitations on the subject matter described. All documents, or portions of documents, cited in this application, including but not limited to patents, patent applications, articles, books, manuals, and treatises, are hereby incorporated by reference in their entirety for any purpose.

Description of drawings

Figure 1 shows the raw data of the experimental results for the inhibition of phosphorylation of the Tyr551 residue of Btk.

Figure 2 shows the analytical data of the experimental results of inhibition of phosphorylation of the Tyr551 residue of Btk.

Detailed ways

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs.

Definitions of standard chemical terms can be found in literature works, including Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY, Fourth Edition, Volumes A (2000) and B (2001), Plenum Press, New York.

It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter as claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. In this application, the use of "or" means "and/or" unless stated otherwise. Furthermore, the use of the term "comprising" as well as other forms, such as "comprising", "containing" and "having", is not limiting.

Definitions of standard chemical terms can be found in literature works, including "ADVANCED ORGANIC CHEMISTRY Fourth Edition" by Carey and Sundberg, Volumes A (2000) and B (2001), Plenum Press, New York. Unless indicated otherwise, conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology, within the skill of the art are employed. Unless specific definitions are provided, the nomenclature used in connection with analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry, and the laboratory procedures and techniques described herein, are those known in the art. Standard techniques are optionally used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation and delivery, and treatment of patients. Standard techniques are optionally used for recombinant DNA, synthetic oligonucleotides, and tissue culture and transformation (eg, electroporation, lipofection). Reactions and purification techniques were performed using documented methods or as described herein.

It is to be understood that the methods and compositions described herein are not limited to the particular methodology, protocols, cell lines, constructs and reagents described herein, but as such may optionally vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the methods and compositions described herein, which will be limited only by the appended claims.

Unless otherwise specified, terms used for complex portions (ie, multi-strand portions) are equivalent whether read from left to right or right to left. For example, the group "alkylenecycloalkylene" means both an alkylene followed by a cycloalkylene or a cycloalkylene followed by an alkylene.

The prefix "ya" added to a group indicates that such a group is divalent. By way of example only, methylene is a divalent group of methyl, ie, it is a -CH2- group; and ethylene is a divalent group of ethyl, ie, -CH2CH2-.

The term "alkyl" as used herein refers to a saturated straight or branched hydrocarbon chain comprising 1-10 carbon atoms, eg 1-6 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neo Pentyl, n-hexyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-di Methylpropyl, 1-methylpropyl, 1-ethylpropyl, 1,2,2-trimethylpropyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3- Dimethylpentyl, n-heptyl, n-octyl, n-nonyl and n-decyl.

"C _1-6 alkyl" means an alkyl group having 1-6 carbon atoms, including methyl, ethyl, propyl, butyl, pentyl and hexyl, including all possible isomeric forms, such as n-propyl And isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl, etc. "C _1-6 alkyl" includes all subranges contained therein, such as C _1-2 alkyl, C _1-3 alkyl, C _1-4 alkyl, C _1-5 alkyl, C _2-5 Alkyl, C _3-5 alkyl, C _4-5 alkyl, C _3-4 alkyl, C _3-5 alkyl and C _4-5 alkyl.

The term "alkylene" refers to a divalent group derived from a saturated straight or branched hydrocarbon chain of 1 to 10 carbon atoms. The term "C _1-6 alkylene" refers to those alkylene groups having 1-6 carbon atoms. Representative examples of alkylene include, but are not limited to, _-CH2- , -CH( _CH3 )-, -CH( _C2H5 ), -CH( _CH ( _CH3 )( _{C2H5 )} )- , -C(H)(CH ₃ )CH ₂ CH ₂ -, -C(CH ₃ ) ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ CH _{2 -} , and -CH2CH( _{CH3 )} CH2-.

"C _1-3 alkylene" includes methylene, ethylene, propylene and isopropylene.

The term "alkenyl" as used herein refers to a straight or branched group containing 2-10 carbons, for example, 2-6 carbons and more preferably 2-4 carbons, and containing at least one carbon-carbon double bond. chain hydrocarbon. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl alkenyl, 2-methyl-1-heptenyl, and 3-decenyl.

"C _2-3 alkenyl" includes ethenyl (-CH=CH ₂ ), propenyl (-CH=CHCH ₃ ) and isopropenyl (-C(CH ₃ )=CH ₂ ).

The term "alkenylene" denotes a divalent radical derived from a straight or branched hydrocarbon chain of 2, 3 or 4 carbon atoms and comprising at least one carbon-carbon double bond. Representative examples of alkenylene include, but are not limited to, -CH= _CH- and -CH2CH=CH-.

"C _2-3 alkenylene" includes ethenylene (-CH=CH-), propenylene (-CH=CHCH ₂ -) and isopropenylene (-C(CH ₃ )=CH-).

The term "alkynyl" as used herein refers to a straight or branched chain hydrocarbon group containing 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond. Representative examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1,1-dimethylprop-2-ynyl, 1-propyl-pent-3-ynyl , 3-butynyl, 2-pentynyl and 1-butynyl.

The term "cycloalkenyl" as used herein refers to a monocyclic or bicyclic ring system containing zero heteroatoms in the ring. Monocyclic cycloalkenyl groups have 3, 4, 5, 6, 7 or 8 carbon atoms and zero heteroatoms. Three or four membered ring systems have 1 double bond, five or six membered ring systems have 1 or 2 double bonds, and seven or eight membered ring systems have 1, 2 or 3 double bonds. Representative examples of monocyclic cycloalkenyl groups include, but are not limited to, cyclohex-1-en-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl, 2,4- Cyclohexadien-1-yl and 3-cyclopenten-1-yl. The bicyclic cycloalkenyl is exemplified by a monocyclic cycloalkenyl fused to a monocyclic cycloalkyl, or a monocyclic cycloalkenyl fused to a monocyclic cycloalkenyl. Non-limiting examples of bicyclic ring systems include 3a,4,5,6,7,7a-hexahydro-1H-indenyl, 4,5,6,7-tetrahydro-3aH-indenyl and octahydronaphthyl . The cycloalkenyl group is attached to the parent molecular moiety through any substitutable carbon atom in the group, and may contain one or two alkylene bridges of 1, 2, 3, or 4 carbon atoms, wherein each bridging group has of two non-adjacent atoms.

As used herein, the term "heterocycle" or "heterocyclic" refers to a monocyclic, bicyclic or spirocyclic ring system containing at least one heteroatom selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, wherein nitrogen and sulfur heteroatoms can be optionally oxidized and nitrogen atoms can be optionally quaternized. A monocyclic heterocycle is a 3, 4, 5, 6, 7 or 8 membered ring containing at least one heteroatom independently selected from O, N and S. The 3- or 4-membered ring contains 1 heteroatom selected from O, N and S, and optionally 1 double bond. The 5 membered ring contains zero or one double bond, and 1, 2 or 3 heteroatoms selected from O, N and S in the ring. The 6-, 7-, or 8-membered ring contains zero, one, or two double bonds, and 1, 2, or 3 heteroatoms selected from O, N, and S in the ring. Examples of monocyclic heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxane Base, 1,4-dioxanyl, 1,3-dioxolyl, 4,5-dihydroisoxazol-5-yl, 3,4-dihydropyran-6 -yl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl , isoxazolidinyl, morpholinyl (including morpholin-4-yl), oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxetanyl, piperazine Base (including piperazin-1-yl), piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl (including tetrahydrofuran-2-yl), tetrahydro Pyranyl, tetrahydrothiophenyl (including tetrahydrothiophen-3-yl), thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-sulfur dioxide Morpholinyl (thiomorpholinyl sulfone), thiopyranyl, dioxide-tetrahydrothiophen-3-yl, and trithianyl. A bicyclic heterocycle is exemplified by a monocyclic heterocycle fused to a phenyl, or a monocyclic heterocycle fused to a monocyclic cycloalkyl, or a monocyclic heterocycle fused to a monocyclic cycloalkenyl , or a monocyclic heterocycle fused to a monocyclic heterocycle. Examples of bicyclic heterocycles include, but are not limited to, 1,3-benzodioxol-4-yl, 1,3-benzodithiol, 2,3-dihydro-1 , 4-benzodioxinyl, 2,3-dihydro-1-benzofuryl, 2,3-dihydro-1-benzothienyl, 2,3-dihydro-1H -indolyl, and 1,2,3,4-tetrahydroquinolinyl. A spiroheterocycle refers to a monocyclic or bicyclic heterocyclic ring in which two substituents on the same carbon atom, together with the carbon atoms, form a 4-, 5- or 6-membered monocyclic cycloalkyl group. An example of a spiroheterocycle is 5-oxaspiro[3,4]octane. The heterocyclic group is attached to the parent molecular moiety through any substitutable carbon atom or any substitutable nitrogen atom contained in the group. A monocyclic or bicyclic heterocyclic group according to the invention may contain an alkenylene bridge of 2, 3 or 4 carbon atoms, or one or two alkylene bridges of 1, 2, 3 or 4 carbon atoms, wherein each bridge connects two non-adjacent carbon atoms in the group. Examples of such bridged heterocycles include, but are not limited to, oxaadamantane (2-oxatricyclo[ ^3.3.1.13,7 ]decane), octahydro-2,5-epoxypentadiene, Hexahydro-2H-2,5-methanocyclopenta[b]furan, Hexahydro-1H-1,4-methanocyclopenta[c]furan, Oxabicyclo [2.2.1] Heptane and 2,4-dioxabicyclo[4.2.1]nonane. The nitrogen and sulfur heteroatoms in the heterocyclic ring can be optionally oxidized (eg, 1,1-tetrahydrothiophenyl dioxide) and the nitrogen atom can be optionally quaternized.

An aromatic group refers to a planar ring having a delocalized pi-electron system and containing 4n+2 pi-electrons, where n is an integer. Aromatic groups may consist of five, six, seven, eight, nine or more than nine ring atoms. Aromatic groups may be optionally substituted. Aromatic groups include "aryl" (ring atoms consisting solely of carbon atoms) and "heteroaryl" (ring atoms consisting of carbon atoms and heteroatoms selected from, for example, oxygen, sulfur and nitrogen). "Aryl" and "heteroaryl" include monocyclic or fused-ring polycyclic (ie, rings that share adjacent pairs of ring atoms) groups.

The term "aryl" as used herein refers to phenyl, bicyclic aryl or tricyclic aryl. The bicyclic aryl is naphthyl, or phenyl fused to a monocyclic cycloalkyl, or phenyl fused to a monocyclic cycloalkenyl. Non-limiting examples of bicyclic aryl groups include indenyl, indenyl, naphthyl, dihydronaphthyl and tetrahydronaphthyl (including 1,2,3,4-tetrahydronaphthalen-1-yl). The tricyclic aryl group is exemplified by a bicyclic aryl group fused to a monocyclic cycloalkyl group, or a bicyclic aryl group fused to a monocyclic cycloalkenyl group, or a bicyclic aryl group fused to a phenyl group. Non-limiting examples of tricyclic aryl groups include anthracene, phenanthrene, dihydroanthracenyl, fluorenyl, 1,2-dihydroacenaphthyl, and tetrahydrophenanthryl. The phenyl, bicyclic and tricyclic aryl are attached to the parent molecular moiety through any carbon atom contained in the phenyl, bicyclic and tricyclic aryl, respectively.

Examples of "aryl" include, but are not limited to, phenyl, naphthyl, phenanthrenyl, anthracenyl, fluorenyl, and indenyl.

The term "heteroaryl" as used herein refers to a monocyclic heteroaryl or a bicyclic heteroaryl. Monocyclic heteroaryl is a 5- or 6-membered ring containing at least one heteroatom independently selected from O, N and S, wherein the nitrogen and sulfur heteroatoms can be optionally oxidized and the nitrogen atom can be optionally oxidized Quarterly. The 5 membered ring contains two double bonds and 1, 2, 3 or 4 heteroatoms. The 6 membered ring contains 3 double bonds and 1, 2, 3 or 4 heteroatoms. Non-limiting examples of monocyclic heteroaryl groups include furyl (including furan-2-yl, furan-3-yl), imidazolyl (including 1H-imidazol-1-yl), isoxazolyl, isothiazolyl , Oxadiazolyl (including 1,2,4-oxadiazol-5-yl), oxazolyl (including 1,3-oxazol-2-yl), pyridyl (including pyridin-2-yl, pyridine -4-yl, pyridin-3-yl), pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl (including thiophene-2- group, thiophen-3-yl), triazolyl and triazinyl. A bicyclic heteroaryl is exemplified by a monocyclic heteroaryl fused to a phenyl, or a monocyclic heteroaryl fused to a monocyclic cycloalkyl, or a monocyclic heteroaryl fused to a monocyclic cycloalkenyl. A ring heteroaryl, or a monocyclic heteroaryl fused to a monocyclic heteroaryl, or a monocyclic heteroaryl fused to a monocyclic heterocycle. Non-limiting examples of bicyclic heteroaryl groups include benzofuryl, benzoxadiazolyl, 1,3-benzothiazolyl, benzimidazolyl, benzodioxolyl, benzothiophene Base, 1H-pyrrolo[2,3-b]pyridinyl (including 1H-pyrrolo[2,3-b]pyridin-4-yl), benzopyranyl, cinnolinyl, furopyridine, ind Indolyl (including 1H-indol-3-yl), indazolyl, isoindolyl, isoquinolyl, naphthyridyl, oxazolopyridine, quinolinyl, thienopyridine and thienopyridyl. The monocyclic and bicyclic heteroaryl groups are attached to the parent molecular moiety through any substitutable carbon atom or any substitutable nitrogen atom contained in the group. The nitrogen heteroatoms of the heteroaryl rings may be optionally oxidized and are contemplated within the scope of this invention.

Examples of "heteroaryl" include:

Wait.

The term "cycloalkyl" as used herein refers to a monocyclic or bicyclic cycloalkyl group, or a spirocyclic cycloalkyl group. Monocyclic cycloalkyls are carbocyclic ring systems comprising 3, 4, 5, 6, 7 or 8 carbon atoms and zero heteroatoms as ring atoms, and zero double bonds. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. A bicyclic cycloalkyl is exemplified by a monocyclic cycloalkyl fused to a monocyclic cycloalkyl. Non-limiting examples of bicyclic cycloalkyls include bicyclo[4.1.0]heptane, bicyclo[6.1.0]nonane, octahydroindene, and decahydronaphthalene. Monocyclic and bicyclic cycloalkyl groups may contain one or two alkylene bridges of 1, 2, 3 or 4 carbon atoms, where each bridge connects two non-adjacent atoms in the group. Examples of such bridged cycloalkyl groups include, but are not limited to, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.3. 1] Nonane, adamantane (tricyclo[ ^3.3.1.13,7 ]decane), and noradamantane (octahydro-2,5-methanopentalene). Spirocycloalkyl is exemplified by monocyclic or bicyclic cycloalkyl in which two substituents on the same carbon atom of the ring, together with the carbon atoms, form a 4-, 5- or 6-membered unit Cycloalkyl rings. An example of a spirocycloalkyl is spiro[2.5]octane. The monocyclic, bicyclic, and spirocyclic cycloalkyl groups are attached to the parent molecular moiety through any substitutable carbon atom of the group.

"C _3-8 cycloalkyl" refers to a non-aromatic group, containing only carbon and hydrogen, and a monocyclic or polycyclic group with ring atoms of 3-8 carbon atoms, and it may be saturated , partially unsaturated or fully unsaturated. Examples of C _3-8 cycloalkyl include the following moieties:

Wait.

"Halogen" refers to fluorine, chlorine, bromine and iodine.

The term "alkoxy" as used herein means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen.

"C _1-6 alkoxy" refers to a (C _1-6 alkyl)O- group, wherein C _1-6 alkyl is as defined herein.

The term "arylalkyl" as used herein means an aryl group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein. Non-limiting examples of arylalkyl include benzyl (phenylmethyl), naphthylmethyl and phenylethyl.

The term "heteroarylalkyl" as used herein means a heteroaryl group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein.

The term "cycloalkylalkyl" as used herein refers to a cycloalkyl group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein.

The term "cycloalkenylalkyl" as used herein means a cycloalkenyl group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein.

The term "heterocycloalkyl" as used herein refers to a heterocyclic group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein.

The term "haloalkyl" as used herein refers to an alkyl group as defined herein wherein 1, 2, 3, 4, 5, 6 or 7 hydrogen atoms are replaced by halogen. Representative examples of haloalkyl include, but are not limited to, chloromethyl, difluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, trifluoromethyl, 2,2,2-trifluoroethyl , 2,2,2-trifluoro-1,1-dimethylethyl, difluoromethyl, 3,3,3-trifluoropropyl, pentafluoroethyl, 2-chloro-3-fluoropentyl , and 2-iodoethyl.

"HaloC _1-6 alkyl" refers to a halo-(C _1-6 alkyl)- group, wherein C _1-6 alkyl is as defined herein. Halogenated C _1-6 alkyl includes perhalogenated C _1-6 alkyl, wherein all hydrogen atoms in C _1-6 alkyl are replaced by halogen, such as -CF ₃ , -CH ₂ CF ₃ , -CF ₂ CF _3. -CH ₂ CH ₂ CF ₃ and so on.

"C _2-3 alkenyl optionally substituted by C _1-3 alkyl" refers to C _2-3 alkenyl or C _2-3 alkenyl substituted by C _1-3 alkyl, wherein through C _{2- 3} The alkenyl group is attached to the main structure of the compound.

"C _1-3 alkyl-NHC(O)-C _2-3 alkenyl" refers to a C _2-3 alkenyl substituted by C _1-3 alkyl-NHC(O)-, wherein through C _2-3 The alkenyl group is attached to the main structure of the compound.

The term "bond" refers to a chemical bond between two atoms, or two moieties, when the atoms joined by the bond are considered to be part of a larger substructure.

As used herein, the term "irreversible inhibitor" refers to a compound that, when contacted with a target protein (such as a kinase), results in the formation of new covalent bonds with or within the protein, thereby weakening or eliminating the One or more biological activities (eg, phosphotransferase activity) of a target protein, regardless of the subsequent presence or absence of an irreversible inhibitor.

As used herein, the term "irreversible Btk inhibitor" refers to an inhibitor of Btk that, in some embodiments, forms a covalent bond with an amino acid residue of Btk. In one embodiment, the irreversible inhibitor of Btk forms a covalent bond with the Cys residue of Btk; The cysteine residues at the cognate counterparts of the acid kinase form a covalent bond.

The term "ester" refers to a chemical moiety having the formula -COOR, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heterocyclyl (bonded through a ring carbon Bond). Any hydroxyl or carboxyl side chain on the compounds described herein can be esterified. Procedures and specific groups for preparing such esters can be found in sources such as Greene and Wuts, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, New York, NY, 1999, the disclosure of which is incorporated in This article is for reference.

The compounds described herein can be formulated and/or used as pharmaceutically acceptable salts. Types of pharmaceutically acceptable salts include, but are not limited to: (1) acid addition salts, formed by reacting the free base form of a compound with a pharmaceutically acceptable inorganic acid such as hydrochloric acid, hydrobromic acid, Sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, etc.; or formed by reaction with organic acids such as acetic acid, propionic acid, caproic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid , malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethyl Alkanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene -1-Formic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid , lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, etc.; (2) salt, when the acidic proton in the parent compound is replaced by a metal ion Formation, for example, of alkali metal ions (eg, lithium, sodium, potassium), alkaline earth metal ions (eg, magnesium or calcium), or aluminum ions; or coordination with organic bases. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, trimethylamine, N-methylglucamine, and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.

As used herein, the term "pharmaceutically acceptable", when referring to a formulation, composition or ingredient, means no lasting adverse effect on the general health of the subject being treated or loss of biological activity or properties of the compound, And relatively non-toxic.

The term "Bruton's tyrosine kinase" as used herein refers to Bruton's tyrosine kinase from Homo sapiens, which has been disclosed in, for example, US Patent No. 6326469 (GenBank Accession No. NP000052).

The term "Bruton's tyrosine kinase homologue" as used herein refers to an ortholog of Bruton's tyrosine kinase, for example from mouse (GenBank accession number AAB47246), dog (GenBank accession number XP_549139), Orthologs of rat (GenBank Accession No. NP_001007799), chicken (GenBank Accession No. NP_989564) or zebrafish (GenBank Accession No. XP_698117), and one or more substrates for Bruton's tyrosine kinase (e.g. A peptide substrate having the amino acid sequence "AVLESEEELYSSARQ") any of the aforementioned fusion proteins exhibiting kinase activity.

The term "administration in combination" or similar terms as used herein includes administration of more than one selected therapeutic agent to a single patient, and includes administration of more than one agent by the same or different routes of administration or at the same or different times treatment plan.

The term "enhancing" means increasing or prolonging the potency or duration of a desired effect. As an example, "enhancing" the effect of a therapeutic agent refers to the ability to increase or prolong the potency or duration of the effect of a therapeutic agent during treatment of a disease, disorder or condition. As used herein, an "enhancing effective amount" refers to an amount sufficient to enhance the effect of a therapeutic agent in the treatment of a disease, disorder or condition. When used in a patient, amounts effective for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.

The term "modulate", as used herein, refers to interacting directly or indirectly with a target so as to alter the activity of the target, including, by way of example only, enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or extending the activity of the target. active. The term "modulator" as used herein refers to a compound that alters the activity of a molecule. For example, a modulator can cause an increase or decrease in the degree of a certain activity of a molecule compared to the degree of that activity in the absence of the modulator. In certain embodiments, a modulator is an inhibitor, which reduces the extent of one or more activities of a molecule. In certain embodiments, an inhibitor completely prevents one or more activities of a molecule. In certain embodiments, a modulator is an activator, which increases the extent of at least one activity of a molecule. In certain embodiments, the presence of a modulator results in activity that is not present in the absence of the modulator.

As used herein, the term "agonist" refers to a compound whose presence results in the same biological activity of a protein (eg, Btk) as the presence of the protein's natural ligand. As used herein, the term "partial agonist" refers to a compound whose presence results in the biological activity of a protein of the same type, but to a lesser degree, than that resulting from the presence of the protein's natural ligand .

As used herein, the term "antagonist" refers to a compound whose presence results in a decreased degree of biological activity of a protein. In certain embodiments, the presence of the antagonist results in complete inhibition of the biological activity of the protein, such as Btk. In certain embodiments, antagonists are inhibitors.

As used herein, "amelioration" of the symptoms of a particular disease, disorder or condition by administration of a particular compound or pharmaceutical composition refers to any reduction in severity, Delay in onset, slowing of progression, or shortening in duration, whether permanent or temporary, continuous or instantaneous.

The DFG-out conformation refers to an inactive conformation of the kinase catalytic domain when the inhibitor binds to the kinase. For more details about the conformation of DFG-out, please refer to the following literature: Wang Yong, Long Yaqiu. New progress in the research of small molecule inhibitors of protein tyrosine kinases [J]. Organic Chemistry, 2011, 31(10): 1595 -1606; and Zhang, Jianming, Priscilla L. Yang, and Nathanael S. Gray. "Targeting cancer with small molecule kinase inhibitors." Nature Reviews Cancer 9.1 (2009): 28-39.

The term "homologous cysteine" as used herein refers to a cysteine residue found within a sequence position homologous to that of cysteine 481 of Bruton's tyrosine kinase as defined herein. For example, cysteine 482 is the homologous cysteine of the rat ortholog of Bruton's tyrosine kinase; cysteine 479 is the homologous cysteine of the chicken ortholog; and Cysteine 481 is the homologous cysteine in the zebrafish ortholog. In another example, the homologous cysteine of TXK, a member of the Tec kinase family related to Bruton's tyrosine, is Cys350. See also the sequence alignment of tyrosine kinases (TKs) published on the world wide web at kinase.com/human/kinome/phylogeny.html.

As used herein, the term "identical" means that two or more sequences or subsequences are identical. Additionally, the term "substantially identical," as used herein, refers to two or more sequences that, when compared and aligned for maximum correspondence within the comparison window, either use a comparison algorithm or measure specified regions by manual alignment and visual inspection , they have a certain percentage of the same sequence units. By way of example only, if the sequence units are about 60% identical, about 65% identical, about 70% identical, about 75% identical, about 80% identical, about 85% identical, about 90% identical over a specified region, % identical, or about 95% identical, then two or more sequences are "substantially identical". Such percentages describe the "percent identity" of two or more sequences. Sequence identity may exist over a region of at least about 75-100 sequence units in length, over a region of about 50 sequence units in length, or, when not specified, over the entire sequence. This definition also refers to the complement of a test sequence. By way of example only, two or more polypeptide sequences are identical when the amino acid residues are the same; whereas the amino acid residues are about 60% identical, about 65% identical, about 70% identical, Two or more polypeptide sequences are "substantially identical" if they are about 75% identical, about 80% identical, about 85% identical, about 90% identical, or about 95% identical. The identity may exist over a region of at least about 75-100 amino acids in length, over a region of about 50 amino acids in length, or, when not specified, the entire sequence of the polypeptide sequence. In addition, by way of example only, two or more polynucleotide sequences are identical when the nucleic acid residues are the same; and if the nucleic acid residues are about 60% identical, about 65% identical, about 70% identical over a specified region, % identical, about 75% identical, about 80% identical, about 85% identical, about 90% identical, or about 95% identical, then two or more polynucleotide sequences are "substantially identical" ". The identity may exist over a region of at least about 75-100 nucleic acids in length, over a region of about 50 nucleic acids in length, or, when not specified, the entire sequence of the polynucleotide sequence.

The term "effective amount" or "therapeutically effective amount" as used herein refers to a sufficient amount of a drug or compound administered which will alleviate to some extent one or more symptoms of the disease or condition being treated. The result can be a reduction and/or alleviation of a sign, symptom or cause of a disease or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is that amount of a composition comprising a compound disclosed herein required to provide a significant reduction in the clinical symptoms of a disease without undue toxic side effects. An "effective amount" appropriate for any individual case can be determined using techniques such as escalation studies. The term "therapeutically effective amount" includes, for example, a prophylactically effective amount. An "effective amount" of a compound disclosed herein is an amount effective to achieve the desired pharmacological effect or therapeutic improvement without undue toxic side effects. It is understood that an "effective amount" or "therapeutically effective amount" may vary from subject to subject due to the metabolism of the compound, the subject's age, weight, general condition, the disease being treated, the severity of the disease being treated Varies in degree and in the judgment of the prescribing physician. By way of example only, a therapeutically effective amount can be determined by routine experimentation, including but not limited to escalation-dose clinical trials.

The term "inhibition", "inhibited" or "inhibitor" of a kinase, as used herein, means that the activity of a phosphotransferase is inhibited.

As used herein, the term "prophylactically effective amount" refers to the amount of a composition applied to a patient which will alleviate to some extent one or more symptoms of the disease, condition or disorder being treated. In such prophylactic applications, such amounts may depend on the patient's state of health, weight, and the like.

As used herein, the term "selective binding compound" refers to a compound that selectively binds to any portion of one or more target proteins.

As used herein, the term "selectively binds" refers to the ability of a selective binding compound to bind a target protein, such as Btk, with a greater affinity than it binds to non-target proteins. In certain embodiments, specific binding refers to binding to a target with an affinity at least 10-fold, 50-fold, 100-fold, 250-fold, 500-fold, 1000-fold or more greater than binding to a non-target.

As used herein, the term "selective modulator" refers to a compound that selectively modulates a target activity relative to a non-target activity. In certain embodiments, a specific modulator refers to modulation of a target activity by at least 10-fold, 50-fold, 100-fold, 250-fold, 500-fold, 1000-fold over a non-target activity.

As used herein, the term "substantially purified" refers to a component of interest that may be substantially or substantially free of other components that normally accompany or interact with the component of interest prior to purification. By way of example only, when the preparation of the target ingredient contains less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 4% %, less than about 3%, less than about 2%, or less than about 1% (by dry weight) of an impurity component, the subject component can be "substantially purified." Thus, a "substantially purified" component of interest may have about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99% or greater purity levels.

The term "individual/subject" as used herein refers to an animal that is the subject of treatment, observation or experimentation. By way of example only, an individual may be, but is not limited to, a mammal, including, but not limited to, a human.

As used herein, the term "target activity" refers to a biological activity capable of being modulated by a selective modulator. Certain exemplary target activities include, but are not limited to, binding affinity, signal transduction, enzymatic activity, tumor growth, inflammation or processes associated with inflammation, and amelioration of one or more symptoms associated with a disease or condition.

As used herein, the term "target protein" refers to a molecule or part of a protein capable of being bound by a selective binding compound. In certain embodiments, the target protein is Btk.

As used herein, the term "treating" includes alleviating, alleviating or ameliorating the symptoms of a disease or condition, preventing additional symptoms, ameliorating or preventing the underlying metabolic cause of the symptoms, inhibiting the disease or condition, such as arresting the development of the disease or condition, relieving the disease or condition, cause a disease or condition to regress, alleviate a condition caused by a disease or condition, or stop the symptoms of a disease or condition. The term "treatment" includes, but is not limited to, prophylactic and/or therapeutic treatment.

As used herein, an IC50 value refers to the amount, concentration or dose of a particular test compound which achieves 50% inhibition of the maximal response in an assay measuring such a response as inhibition of Btk.

As used herein, an EC50 value refers to the dose, concentration or amount of a specific test compound that elicits a dose-dependent response that is 50% of the maximal expression of the specific response induced, elicited or potentiated by the specific test compound.

Autoimmune diseases described herein include, but are not limited to, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, lupus, diabetes, myasthenia gravis, Hashimoto's Thyroiditis, Oder's thyroiditis, Graves' disease, rheumatoid arthritis syndrome, multiple sclerosis, infectious neuronitis, acute disseminated encephalomyelitis, Addison's disease, optic clonus - Myoclonus syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, Goodpasture syndrome, idiopathic thrombocytopenic purpura, optic neuritis, Scleroderma, primary biliary cirrhosis, Reiter syndrome, Takayasu arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, generalized alopecia, Baycher Cheeter's disease, chronic fatigue, familial dysautonomia, endometriosis, interstitial cystitis, neuromuscular rigidity, scleroderma, and vulvodynia.

The heteroimmune diseases described herein include, but are not limited to, graft-versus-host disease, transplantation, blood transfusion, allergic reactions, allergic reactions (such as to plant pollen, latex, drugs, food, insect poisons, animal hair, animal dander, dust mite or cockroach calyx), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis.

Inflammatory diseases described herein include, but are not limited to, asthma, inflammatory bowel disease, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, Cystitis, lacrimal gland inflammation, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastrointestinal Inflammation, hepatitis, hidradenitis suppurativa, laryngitis, mastitis, meningitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, peritonitis, Pharyngitis, pleurisy, phlebitis, localized pneumonia (pneumonitis), pneumonia (pneumonia), proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, Uveitis, vaginitis, vasculitis and vulvitis.

Cancers such as B-cell proliferative disorders described herein include, but are not limited to, diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphocytic Plasma cell lymphoma/Waldenstrom macroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B-cell lymphoma, lymph node marginal zone B-cell lymphoma, mantle Cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt lymphoma/leukemia, and lymphomatoid granulomatous disease.

Thromboembolic disorders as described herein include, but are not limited to, myocardial infarction, angina (including unstable angina), reocclusion or restenosis after angioplasty or aortocoronary bypass, stroke, transient ischemia, Peripheral arterial occlusive disease, pulmonary embolism, and deep vein thrombosis.

Mastocytosis as described herein includes, but is not limited to, diseases characterized by hyperactive mast cells.

Osteoporosis or bone resorption disorders as described herein include, but are not limited to, Paget's disease of bone, osteoporosis, and bone changes secondary to cancer, such as occurs in myeloma and Metastasis from breast cancer.

Symptoms, diagnostic assays, and prognostic assays for each of the above mentioned diseases are known in the art. See e.g. Harrison's Principles of Internal 16th Edition, 2004, The McGraw-Hill Companies, Inc. Dey et al. (2006), Cytojournal3 (24) and the Revised European American Lymphoma (REAL) classification system (see eg the website operated by the National Cancer Institute).

In the first aspect of the compound of the present invention, the present invention provides a compound of formula (IA), or its pharmaceutically active metabolite, pharmaceutically acceptable solvate, pharmaceutically acceptable salt, pharmaceutically acceptable Acceptable esters, or pharmaceutically acceptable prodrugs, or tautomeric forms thereof, or isotopically substituted forms thereof (including, but not limited to, for example, ² H in place of ¹ H, and ¹⁸ F in place of ¹⁹ F) :

in,

R ₁ and R ₂ are independently of each other, identically or differently, selected from: hydrogen (when L ₁ or L ₂ does not exist), -C(O)-, -C(S)-, -C(O) O-, -OC(O)-, -N(R ^d )C(O)-, -C(O)N(R ^d )-, -S(O)-, -S(O) ₂ -, - S(O) ₂ N(R ^d )-, -N(R ^d )S(O) ₂ -, or -C(=NR ^a )-;

L ¹ and L ² are independently of each other, identical or different, selected from: absent, hydrogen, C _2-10 alkenyl, C _2-10 alkenyl substituted by C _1-6 alkyl, -C _{1- 3} Alkyl-NHC(O)-C _2-10 Alkenyl, -C _1-3 Alkyl-C(O)-C _2-10 Alkenyl, -C _1-3 Alkyl-C(S)-C _2-10 alkenyl, -C _1-3 alkyl-C (O) OC _2-10 alkenyl, -C _1-3 alkyl-OC (O) -C _2-10 alkenyl, -C _1-3 Alkyl-NHC(O)-C _2-10 alkenyl, -C _1-3 alkyl-C(O)NH-C _2-10 alkenyl, -C _1-3 alkyl-S(O)-C _2-10 alkenyl, -C _1-3 alkyl-S (O) ₂ -C _2-10 alkenyl, -C _1-3 alkyl-S (O) ₂ NH-C _2-10 alkenyl, - C _1-3 alkyl-NHS(O) ₂ -C _2-10 alkenyl, -C _1-3 alkyl-C(=NH)-C _2-10 alkenyl, the above C _2-10 alkenyl can be Optionally substituted one or more times by substituents independently selected from halogen, R ^a O- and R ^b R ^c N- at positions that can be substituted; the above-mentioned C _1-3 alkyl and C _1-6 alkane The radicals are independently selected from one or two independently selected from alkyl, alkenyl, alkynyl, halogen, -NO ₂ , -CN, haloalkyl, -OR ^a , -OC(O)R ^a , -NR ^a R ^b , -N(R ^b )C(O)R ^a , -N(R ^b )S(O) ₂ R ^a , -SR ^a , -S(O)R ^c , -S(O) ₂ R ^c , -S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -(C _1-6 alkylene)- NO ₂ ,-(C _1-6 alkylene)-CN,-(C _1-6 alkylene)-OR ^a ,-(C _1-6 alkylene)-OC(O)R ^a ,-( C _1-6 alkylene)-NR ^a R ^b , -(C _1-6 alkylene)-N(R ^b )C(O)R ^a ,-(C _1-6 alkylene)-N( R ^b )S(O) ₂ R ^a ,-(C _1-6 alkylene)-SR ^a ,-(C _1-6 alkylene)-S(O)R ^c ,-(C _1-6 alkylene Alkyl)-S(O) ₂ R ^c , -(C _1-6 alkylene)-S(O) ₂ NR ^a R ^b ,-(C _1-6 alkylene)-C(O)R ^a , -(C _1-6 alkylene)-C(O)OR ^a , or -(C _1-6 alkylene)-C(O)NR ^a R ^b group substitution; C _2-10 alkynyl , C _2-10 alkynyl substituted by C _1-6 alkyl, -C _1-3 alkyl-NHC(O)-C _2-10 alkynyl, -C _1-3 alkyl-C(O)-C _2-10 alkynyl, -C _1-3 alkyl-C(S)-C _2-10 alkynyl, -C _{1- 3} Alkyl-C(O)OC _2-10 Alkynyl, -C _1-3 Alkyl-OC(O)-C _2-10 Alkynyl, -C _1-3 Alkyl-NHC(O)-C _{2 -10} alkynyl, -C _1-3 alkyl-C(O)NH-C _2-10 alkynyl, -C _1-3 alkyl-S(O)-C _2-10 alkynyl, -C _{1- 3} alkyl-S (O) ₂ -C _2-10 alkynyl, -C _1-3 alkyl-S (O) ₂ NH-C _2-10 alkynyl, -C _1-3 alkyl-NHS (O ) ₂ -C _2-10 alkynyl, or -C _1-3 alkyl-C(=NH)-C _2-10 alkynyl, the above-mentioned C _2-10 alkynyl can optionally be substituted Substituted one or more times by substituents independently selected from halogen, R ^a O- and R ^b R ^c N-; the above-mentioned C _1-3 alkyl and C _1-6 alkyl are independently optionally replaced by 1 or 2 independently selected from alkyl, alkenyl, alkynyl, halogen, -NO ₂ , -CN, haloalkyl, -OR ^a , -OC(O)R ^a , -NR ^a R ^b , -N(R ^b )C(O)R ^a , -N(R ^b )S(O) ₂ R ^a , -SR ^a , -S(O)R ^c , -S(O) ₂ R ^c , -S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -(C _1-6 alkylene)-NO ₂ , -(C _1-6 Alkylene)-CN,-(C _1-6 alkylene)-OR ^a ,-(C _1-6 alkylene)-OC(O)R ^a ,-(C _1-6 alkylene)- NR ^a R ^b , -(C _1-6 alkylene)-N(R ^b )C(O)R ^a , -(C _1-6 alkylene)-N(R ^b )S(O) ₂ R ^a ,-(C _1-6 alkylene)-SR ^a ,-(C _1-6 alkylene)-S(O)R ^c ,-(C _1-6 alkylene)-S(O) ₂ R ^c , -(C _1-6 alkylene)-S(O) ₂ NR ^a R ^b , -(C _1-6 alkylene)-C(O)R ^a , -(C _1-6 alkylene Base) -C (O) OR ^a , or - (C _1-6 alkylene) -C (O) NR ^a R ^b group substitution;

R ₃ is selected from: hydrogen, alkyl, alkenyl, alkynyl, -(C _1-6 alkylene)-NO ₂ , -(C _1-6 alkylene)-CN, -(C _1-6 alkylene Alkyl)-OR ^a ,-(C _1-6 alkylene)-OC(O)R ^a ,-(C _1-6 alkylene)-NR ^a R ^b ,-(C _1-6 alkylene )-N(R ^b )C(O)R ^a ,-(C _1-6 alkylene)-N(R ^b )S(O) ₂ R ^a ,-(C _1-6 alkylene)-SR ^a ，-(C _1-6 alkylene)-S(O)R ^c ，-(C _1-6 alkylene)-S(O) ₂ R ^c ，-(C _1-6 alkylene)- S(O) ₂ NR ^a R ^b , -(C _1-6 alkylene)-C(O)R ^a , -(C _1-6 alkylene)-C(O)OR ^a , or -(C _1-6 alkylene)-C(O)NR ^a R ^b ;

R ₄ is selected from: hydrogen, alkyl, alkenyl, alkynyl, -(C _1-6 alkylene)-NO ₂ , -(C _1-6 alkylene)-CN, -(C _1-6 alkylene Alkyl)-OR ^a ,-(C _1-6 alkylene)-OC(O)R ^a ,-(C _1-6 alkylene)-NR ^a R ^b ,-(C _1-6 alkylene )-N(R ^b )C(O)R ^a ,-(C _1-6 alkylene)-N(R ^b )S(O) ₂ R ^a ,-(C _1-6 alkylene)-SR ^a ，-(C _1-6 alkylene)-S(O)R ^c ，-(C _1-6 alkylene)-S(O) ₂ R ^c ，-(C _1-6 alkylene)- S(O) ₂ NR ^a R ^b , -(C _1-6 alkylene)-C(O)R ^a , -(C _1-6 alkylene)-C(O)OR ^a , or -(C _1-6 alkylene)-C(O)NR ^a R ^b ;

Z ₁ at each occurrence is independently selected from: alkyl, alkenyl, alkynyl, halogen, -NO ₂ , -CN, haloalkyl, -OR ^a , -OC(O)R ^a , -NR ^a R ^b , -N(R ^b )C(O)R ^a , -N(R ^b )S(O) ₂ R ^a , -SR ^a , -S(O)R ^c , -S(O) ₂ R ^c , -S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -(C _1-6 alkylene)-NO ₂ ,-(C _1-6 alkylene)-CN,-(C _1-6 alkylene)-OR ^a ,-(C _1-6 alkylene)-OC(O)R ^a ,-(C _{1 -6} alkylene)-NR ^a R ^b , -(C _1-6 alkylene)-N(R ^b )C(O)R ^a ,-(C _1-6 alkylene)-N(R ^b )S(O) ₂ R ^a ,-(C _1-6 alkylene)-SR ^a ,-(C _1-6 alkylene)-S(O)R ^c ,-(C _1-6 alkylene )-S(O) ₂ R ^c ,-(C _1-6 alkylene)-S(O) ₂ NR ^a R ^b ,-(C _1-6 alkylene)-C(O)R ^a ,- (C _1-6 alkylene)-C(O)OR ^a , or -(C _1-6 alkylene)-C(O)NR ^a R ^b ; or aryl, heteroaryl, cycloalkyl, Cycloalkenyl, heterocycle, arylalkyl, heteroarylalkyl, cycloalkylalkyl, cycloalkenylalkyl, or heterocycloalkyl; where aryl, heteroaryl, cycloalkyl, cycloalkene Each of the group and the heterocyclic moiety, as a substituent or part of a substituent, is independently unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents as represented by R ^z ;

m1 is 0, 1, 2, 3 or 4,

n is 0, 1, 2, 3 or 4,

The condition is m1+n≤4,

Z ₂ are each independently selected from each occurrence: alkyl, alkenyl, alkynyl, halogen, -NO ₂ , -CN, haloalkyl, -OR ^a , -OC(O)R ^a , -NR ^a R ^b , -N(R ^b )C(O)R ^a , -N(R ^b )S(O) ₂ R ^a , -SR ^a , -S(O)R ^c , -S(O) ₂ R ^c , -S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -(C _1-6 alkylene)-NO ₂ ,-(C _1-6 alkylene)-CN,-(C _1-6 alkylene)-OR ^a ,-(C _1-6 alkylene)-OC(O)R ^a ,-(C _{1 -6} alkylene)-NR ^a R ^b , -(C _1-6 alkylene)-N(R ^b )C(O)R ^a ,-(C _1-6 alkylene)-N(R ^b )S(O) ₂ R ^a ,-(C _1-6 alkylene)-SR ^a ,-(C _1-6 alkylene)-S(O)R ^c ,-(C _1-6 alkylene )-S(O) ₂ R ^c ,-(C _1-6 alkylene)-S(O) ₂ NR ^a R ^b ,-(C _1-6 alkylene)-C(O)R ^a ,- (C _1-6 alkylene)-C(O)OR ^a , or -(C _1-6 alkylene)-C(O)NR ^a R ^b ;

m2 is 0, 1 or 2,

Z ₃ are each independently selected from each occurrence of: alkyl, alkenyl, alkynyl, halogen, -NO ₂ , -CN, haloalkyl, -OR ^a , -OC(O)R ^a , -NR ^a R ^b , -N(R ^b )C(O)R ^a , -N(R ^b )S(O) ₂ R ^a , -SR ^a , -S(O)R ^c , -S(O) ₂ R ^c , -S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -(C _1-6 alkylene)-NO ₂ ,-(C _1-6 alkylene)-CN,-(C _1-6 alkylene)-OR ^a ,-(C _1-6 alkylene)-OC(O)R ^a ,-(C _{1 -6} alkylene)-NR ^a R ^b , -(C _1-6 alkylene)-N(R ^b )C(O)R ^a ,-(C _1-6 alkylene)-N(R ^b )S(O) ₂ R ^a ,-(C _1-6 alkylene)-SR ^a ,-(C _1-6 alkylene)-S(O)R ^c ,-(C _1-6 alkylene )-S(O) ₂ R ^c ,-(C _1-6 alkylene)-S(O) ₂ NR ^a R ^b ,-(C _1-6 alkylene)-C(O)R ^a ,- (C _1-6 alkylene)-C(O)OR ^a , or -(C _1-6 alkylene)-C(O)NR ^a R ^b ; or aryl, heteroaryl, cycloalkyl, Cycloalkenyl, heterocycle, arylalkyl, heteroarylalkyl, cycloalkylalkyl, cycloalkenylalkyl, or heterocycloalkyl; where aryl, heteroaryl, cycloalkyl, cycloalkene Each of the group and the heterocyclic moiety, as a substituent or part of a substituent, is independently unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents as represented by R ^z ;

m3 is 0, 1, 2, 3, 4 or 5,

R ^d each occurrence is independently selected from: hydrogen or alkyl, which is optionally selected from 1 or 2 independently selected from -OH, -O(alkyl), halogen, -C(O)(alkyl ), -C(O)O(alkyl), -C(O)NH ₂ , -C(O)N(H)(alkyl), -C(O)N(alkyl) ₂ , cycloalkyl , cycloalkenyl, heterocycle, aryl, and heteroaryl substituents;

R ^z is independently selected from each occurrence of each other: alkyl, alkenyl, alkynyl, halogen, -NO ₂ , -CN, haloalkyl, -OR ^a , -OC(O)R ^a , -NR ^a R ^b , -N(R ^b )C(O)R ^a , -N(R ^b )S(O) ₂ R ^a , -SR ^a , -S(O)R ^c , -S(O) ₂ R ^c , -S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -(C _1-6 alkylene)-NO ₂ ,-(C _1-6 alkylene)-CN,-(C _1-6 alkylene)-OR ^a ,-(C _1-6 alkylene)-OC(O)R ^a ,-(C _{1 -6} alkylene)-NR ^a R ^b , -(C _1-6 alkylene)-N(R ^b )C(O)R ^a ,-(C _1-6 alkylene)-N(R ^b )S(O) ₂ R ^a ,-(C _1-6 alkylene)-SR ^a ,-(C _1-6 alkylene)-S(O)R ^c ,-(C _1-6 alkylene )-S(O) ₂ R ^c ,-(C _1-6 alkylene)-S(O) ₂ NR ^a R ^b ,-(C _1-6 alkylene)-C(O)R ^a ,- (C _1-6 alkylene)-C(O)OR ^a , or -(C _1-6 alkylene)-C(O)NR ^a R ^b ;

Each ^occurrence of R is independently selected from: hydrogen, alkyl, or haloalkyl;

Each occurrence of R ^b is independently selected from: hydrogen, alkyl, or haloalkyl;

Each occurrence of R ^c is independently selected from: hydrogen, alkyl, or haloalkyl.

According to the above aspects of the present invention, the following specific embodiments are further provided. These embodiments can be combined with each other to constitute embodiments in the above aspects of the present invention.

In one embodiment, the compound of formula (I-A) is a compound of formula (I-B) or formula (I-C):

wherein R ₁ , R ₂ , R ₃ , R ₄ , L ₁ , L ₂ , Z ₁ , Z ₂ , Z ₃ , m1, m2, and m3 are as defined above.

In one embodiment, n=0.

_{In one} embodiment, R and R are independently of each other, identical or different, selected from: hydrogen (when L or L is absent), _-C (O) _- , -C(S) -, -C(O)O-, -OC(O)-, -NHC(O)-, -C(O)NH-, -S(O)-, -S(O) ₂ -, -S( O) ₂ NH-, -NHS(O) ₂ -, or -C(=NH)-.

In ^one embodiment, L and L are independently of each other, identical or different, selected from: absent, hydrogen, C ^2-10 alkenyl, C _2-10 substituted by C _{1-6 alkyl} Alkenyl, -C _1-3 alkyl-NHC(O)-C _2-10 alkenyl, -C _1-3 alkyl-C(O)-C _2-10 alkenyl, -C _1-3 alkyl -C(S)-C _2-10 alkenyl, -C _1-3 alkyl-C(O)OC _2-10 alkenyl, -C _1-3 alkyl-OC(O)-C _2-10 alkenyl Base, -C _1-3 Alkyl-NHC(O)-C _2-10 Alkenyl, -C _1-3 Alkyl-C(O)NH-C _2-10 Alkenyl, -C _1-3 Alkyl -S(O)-C _2-10 alkenyl, -C _1-3 alkyl-S(O) ₂ -C _2-10 alkenyl, -C _1-3 alkyl-S(O) ₂ NH-C _2-10 alkenyl, -C _1-3 alkyl-NHS(O) ₂ -C _2-10 alkenyl, or -C _1-3 alkyl-C(=NH)-C _2-10 alkenyl; above The C _2-10 alkenyl can optionally be substituted one or more times at the position that can be substituted by a substituent independently selected from halogen, R ^a O- and R ^b R ^c N-; the above C _1-3 Alkyl and C _1-6 alkyl are independently selected from each other by 1 or 2 independently selected from alkyl, alkenyl, alkynyl, halogen, -NO ₂ , -CN, haloalkyl, -OR ^a , -OC (O)R ^a , -NR ^a R ^b , -N(R ^b )C(O)R ^a , -N(R ^b )S(O) ₂ R ^a , -SR ^a , -S(O)R ^c , -S(O) ₂ R ^c , -S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -(C _1-6 alkylene)-NO ₂ ,-(C _1-6 alkylene)-CN,-(C _1-6 alkylene)-OR ^a ,-(C _1-6 alkylene)-OC (O)R ^a ,-(C _1-6 alkylene)-NR ^a R ^b ,-(C _1-6 alkylene)-N(R ^b )C(O)R ^a ,-(C _{1- 6} alkylene)-N(R ^b )S(O) ₂ R ^a , -(C _1-6 alkylene)-SR ^a ,-(C _1-6 alkylene)-S(O)R ^c ,-(C _1-6 alkylene)-S(O) ₂ R ^c ,-(C _1-6 alkylene)-S(O) ₂ NR ^a R ^b ,-(C _1-6 alkylene )-C(O)R ^a , -(C _1-6 alkylene)-C(O)OR ^a , or -(C _1-6 alkylene)-C(O)NR ^a R ^b group replace;.

In one embodiment, R ₃ is selected from: hydrogen, or -C _1-10 alkyl, -C _2-10 alkenyl, -C _2-10 alkynyl.

In one embodiment, R ₄ is selected from: hydrogen, or -C _1-10 alkyl, -C _2-10 alkenyl, -C _2-10 alkynyl.

In one embodiment, Z ₁ , Z ₂ and Z ₃ are each independently selected from each occurrence of: -C _1-10 alkyl, -C _2-10 alkenyl, -C _2-10 alkynyl, Halogen, -NO ₂ , -CN, halogenated C _1-10 alkyl, -OR ^a , -OC(O)R ^a , -NR ^a R ^b , -N(R ^b )C(O)R ^a , - N(R ^b )S(O) ₂ R ^a , -SR ^a , -S(O)R ^c , -S(O) ₂ R ^c , -S(O) ₂ NR ^a R ^b , -C(O) R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -(C _1-6 alkylene)-NO ₂ , -(C _1-6 alkylene)-CN, -( C _1-6 alkylene)-OR ^a ,-(C _1-6 alkylene)-OC(O)R ^a ,-(C _1-6 alkylene)-NR ^a R ^b ,-(C _{1 -6} alkylene)-N(R ^b )C(O)R ^a ,-(C _1-6 alkylene)-N(R ^b )S(O) ₂ R ^a ,-(C _1-6 alkylene Alkyl)-SR ^a ,-(C _1-6 alkylene)-S(O)R ^c ,-(C _1-6 alkylene)-S(O) ₂ R ^c ,-(C _1-6 Alkylene)-S(O) ₂ NR ^a R ^b , -(C _1-6 alkylene)-C(O)R ^a ,-(C _1-6 alkylene)-C(O)OR ^a , or -(C _1-6 alkylene)-C(O)NR ^a R ^b ; or phenyl, 5 or 6 membered heteroaryl, C _3-8 cycloalkyl, heterocycle, benzyl, C _{3 -8} cycloalkyl C _1-10 alkyl, or heterocycle-C _1-10 alkyl;

In one embodiment m1, m2 and m3 are 0, 1 or 2 independently of each other.

In one embodiment, each ^occurrence of R is independently selected from: hydrogen or C _1-10 alkyl;

In one embodiment, each ^occurrence of R is independently selected from: hydrogen or C _1-10 alkyl;

In one embodiment, each occurrence of R ^c is independently selected from each other: hydrogen or C _1-10 alkyl.

In the first aspect of the compound of the present invention, the present invention provides: the compound of formula (I), or its pharmaceutically active metabolite, pharmaceutically acceptable solvate, pharmaceutically acceptable salt, pharmaceutically acceptable Acceptable esters, or pharmaceutically acceptable prodrugs, or tautomeric forms thereof, or isotopically substituted forms thereof (including, but not limited to, for example, ² H in place of ¹ H, and ¹⁸ F in place of ¹⁹ F):

in,

W is selected from H, C _1-6 alkyl (the above C _1-6 alkyl is optionally selected from 1 or 2 independently selected from alkyl, alkenyl, alkynyl, halogen, -NO ₂ , -CN, haloalkane base, -OR ^a , -OC(O)R ^a , -NR ^a R ^b , -N(R ^b )C(O)R ^a , -N(R ^b )S(O) ₂ R ^a , -SR ^a , -S(O)R ^c , -S(O) ₂ R ^c , -S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a , -C(O) NR ^a R ^b , -(C _1-6 alkylene) -NO ₂ , -(C _1-6 alkylene) -CN, -(C _1-6 alkylene) -OR ^a , -(C _{1 -6} alkylene)-OC(O)R ^a ,-(C _1-6 alkylene)-NR ^a R ^b ,-(C _1-6 alkylene)-N(R ^b )C(O) R ^a ,-(C _1-6 alkylene)-N(R ^b )S(O) ₂ R ^a ,-(C _1-6 alkylene)-SR ^a ,-(C _1-6 alkylene )-S(O)R ^c ,-(C _1-6 alkylene)-S(O) ₂ R ^c ,-(C _1-6 alkylene)-S(O) ₂ NR ^a R ^b ,- (C _1-6 alkylene)-C(O)R ^a , -(C _1-6 alkylene)-C(O)OR ^a , or -(C _1-6 alkylene)-C(O ) group substitution of NR ^a R ^b ; R ^a at each occurrence is independently selected from: hydrogen or C _1-10 alkyl; R ^b at each occurrence is independently selected from: hydrogen or C _{1- 10} alkyl; each occurrence of R ^c is independently selected from each other: hydrogen or C _1-10 alkyl), -(NH-CO) _n -LL ₃ , -(CO-NH) _n -LL ₃ , and -(NH-CO) _n -NH-LL ₃ ,

in

L is a bond, C _1-3 alkylene, or C _2-3 alkenylene,

L ₃ is C _3-8 cycloalkyl, aryl, or heteroaryl optionally substituted by 1, 2 or 3 substituents selected from the group consisting of: halogen, amino, C _1-6 alkyl, C _{1 -6} alkoxy, halogenated C _1-6 alkyl (the above-mentioned C _1-6 alkyl, C _1-6 alkoxy, the C _1-6 alkyl in halogenated C _1-6 alkyl is optional 1 or 2 independently selected from alkyl, alkenyl, alkynyl, halogen, -NO ₂ , -CN, haloalkyl, -OR ^a , -OC(O)R ^a , -NR ^a R ^b , -N (R ^b )C(O)R ^a , -N(R ^b )S(O) ₂ R ^a , -SR ^a , -S(O)R ^c , -S(O) ₂ R ^c , -S(O ) ₂ NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -(C _1-6 alkylene)-NO ₂ , -(C _1-6 alkylene)-CN,-(C _1-6 alkylene)-OR ^a ,-(C _1-6 alkylene)-OC(O)R ^a ,-(C _1-6 alkylene base)-NR ^a R ^b ,-(C _1-6 alkylene)-N(R ^b )C(O)R ^a ,-(C _1-6 alkylene)-N(R ^b )S(O ) ₂ R ^a , -(C _1-6 alkylene)-SR ^a , -(C _1-6 alkylene)-S(O)R ^c , -(C _1-6 alkylene)-S( O) ₂ R ^c , -(C _1-6 alkylene) -S(O) ₂ NR ^a R ^b , -(C _1-6 alkylene) -C(O)R ^a , -(C _{1- 6} alkylene) -C (O) OR ^a , or - (C _1-6 alkylene) -C (O) NR ^a group substitution of R ^b ; R ^a in each occurrence is independently selected from : hydrogen or C _1-10 alkyl; R ^b is independently selected from each occurrence: hydrogen or C _1-10 alkyl; R ^c is independently selected from each occurrence: hydrogen or C _{1- 10} alkyl),

n is an integer 0 or 1,

X is selected from H, halogen, and C _1-6 alkyl (the above C _1-6 alkyl is optionally selected from 1 or 2 independently selected from alkyl, alkenyl, alkynyl, halogen, -NO ₂ , - CN, haloalkyl, -OR ^a , -OC(O)R ^a , -NR ^a R ^b , -N(R ^b )C(O)R ^a , -N(R ^b )S(O) ₂ R ^a , -SR ^a , -S(O)R ^c , -S(O) ₂ R ^c , -S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a , -C (O)NR ^a R ^b ,-(C _1-6 alkylene)-NO ₂ ,-(C _1-6 alkylene)-CN,-(C _1-6 alkylene)-OR ^a ,- (C _1-6 alkylene)-OC(O)R ^a ,-(C _1-6 alkylene)-NR ^a R ^b ,-(C _1-6 alkylene)-N(R ^b )C (O)R ^a ,-(C _1-6 alkylene)-N(R ^b )S(O) ₂ R ^a ,-(C _1-6 alkylene)-SR ^a ,-(C _1-6 Alkylene)-S(O)R ^c , -(C _1-6 alkylene)-S(O) ₂ R ^c ,-(C _1-6 alkylene)-S(O) ₂ NR ^a R ^b , -(C _1-6 alkylene)-C(O)R ^a , -(C _1-6 alkylene)-C(O)OR ^a , or -(C _1-6 alkylene)- C (O) NR ^a group substitution of R ^b ; R ^a each occurrence is independently selected from: hydrogen or C _1-10 alkyl; R ^b each occurrence is independently selected from: hydrogen or C _1-10 alkyl; R ^c independently of each other at each occurrence is selected from: hydrogen or C _1-10 alkyl),

R ₁ and R ₂ are independently of each other, identically or differently, selected from H, C(O) and S(O) ₂ ;

L and L are independently _of each other, identically or differently, selected from C _{2-3 alkenyl} optionally substituted by C _1-3 alkyl, and C _1-3 alkyl-NHC(O)-C _2-3 alkenyl, wherein "C _2-3 alkenyl optionally substituted by C _1-3 alkyl" and "C _1-3 alkyl-NHC(O)-C _2-3 alkenyl" The above-mentioned C _1-3 alkyl is optionally selected from 1 or 2 independently selected from alkyl, alkenyl, alkynyl, halogen, -NO ₂ , -CN, haloalkyl, -OR ^a , -OC(O)R ^a , -NR ^a R ^b , -N(R ^b )C(O)R ^a , -N(R ^b )S(O) ₂ R ^a , -SR ^a , -S(O)R ^c , -S( O) ₂ R ^c , -S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -(C _1-6 Alkyl)-NO ₂ ,-(C _1-6 alkylene)-CN,-(C _1-6 alkylene)-OR ^a ,-(C _1-6 alkylene)-OC(O)R ^a ,-(C _1-6 alkylene)-NR ^a R ^b ,-(C _1-6 alkylene)-N(R ^b )C(O)R ^a ,-(C _1-6 alkylene )-N(R ^b )S(O) ₂ R ^a ,-(C _1-6 alkylene)-SR ^a ,-(C _1-6 alkylene)-S(O)R ^c ,-(C _1-6 alkylene)-S(O) ₂ R ^c , -(C _1-6 alkylene)-S(O) ₂ NR ^a R ^b ,-(C _1-6 alkylene)-C( O) R ^a , -(C _1-6 alkylene)-C(O)OR ^a , or -(C _1-6 alkylene)-C(O)NR ^a R ^b group substitution; R ^a independently at each occurrence from: hydrogen or C _1-10 alkyl; R ^b independently at each occurrence from: hydrogen or ^C _1-10 alkyl; R at each occurrence from each other independently selected from: hydrogen or C _1-10 alkyl;

The premise is that when R ₁ is H, L ₁ is absent, and when R ₂ is H, L ₂ is absent.

According to the above aspects of the present invention, the following specific embodiments are further provided.

In one embodiment, W is selected from H, ethyl, -(NH-CO) _n -LL ₃ , -(CO-NH) _n -LL ₃ , and -(NH-CO) _n -NH-LL ₃ , wherein L is a bond or vinylidene, L3 is cyclopropyl, phenyl, naphthyl optionally substituted by 1 or ₂ substituents selected from F, C1, amino, methoxy, and _CF3 , isoxazolyl or benzo[d][1,3]dioxolyl, n is an integer 1.

In one embodiment, X is selected from H, F, Cl, and methyl.

In one embodiment, R ₁ and R ₂ are independently of each other, identical or different, selected from H, C(O) and S(O) ₂ ; L ₁ and L ₂ are independently of each other, identical or different is selected from C _2-3 alkenyl, and methyl-NHC(O)-vinyl; provided that when R ₁ is H, L ₁ is absent, and when R ₂ is H, L ₂ is absent.

In one embodiment, W is selected from H, ethyl, -(NH-CO) _n -LL ₃ , -(CO-NH) _n -LL ₃ , and -(NH-CO) _n -NH-LL ₃ , wherein L is a bond or vinylidene, _L is cyclopropyl, phenyl, naphthyl optionally substituted by 1 or ₂ substituents selected from F, Cl, amino, methoxy, and CF , isoxazolyl or benzo[d][1,3]dioxolyl, n is an integer ₁ , X is selected from H, F, Cl, and methyl, R and _R are independently of each other , identically or differently, selected from H, C(O) and S(O) ₂ ; L ₁ and L ₂ independently of each other, identically or differently, selected from C _2-3 alkenyl, and methyl- NHC(O)-vinyl; provided that when R ₁ is H, L ₁ is absent, and when R ₂ is H, L ₂ is absent.

In a third aspect of the compounds of the present invention, the present invention provides a compound selected from the group consisting of, or a pharmaceutically active metabolite, a pharmaceutically acceptable solvate, a pharmaceutically acceptable salt, a pharmaceutically acceptable Esters, or pharmaceutically acceptable prodrugs, or tautomeric forms thereof, or isotopically substituted forms thereof (including, but not limited to, for example, ² H instead of ¹ H, and ¹⁸ F instead of ¹⁹ F):

In a fourth aspect of the compounds of the invention, also described herein are irreversible inhibitors of Btk. Irreversible inhibitors of Btk that form covalent bonds with cysteine residues on Btk are further described. Further described herein are irreversible inhibitors of other tyrosine kinases, wherein the other tyrosine kinases have the same properties as Btk by having cysteine residues (including the Cys481 residue) that can form a covalent bond with the irreversible inhibitors. (such tyrosine kinases are referred to herein as "Btk tyrosine kinase cysteine homologs"). Also described herein are tyrosine kinases having accessible cysteine residues near the active site of the tyrosine kinase (referred to herein as "accessible cysteine kinases" or ACKs). irreversible inhibitors.

Also described herein, in the relevant section below, are methods for the synthesis of such irreversible inhibitors for use in the treatment of diseases, including diseases in which irreversible inhibition of Btk provides a therapeutic benefit to patients suffering from the disease Methods. Pharmaceutical formulations comprising irreversible inhibitors of Btk are further described.

In further or alternative embodiments, the compounds of the invention are selective irreversible inhibitors of Btk relative to Itk. In further or alternative embodiments, the compounds of the invention are selective irreversible inhibitors of Btk relative to Lck. In further or alternative embodiments, the compounds of the invention are selective irreversible inhibitors of Btk relative to ABL. In further or alternative embodiments, the compounds of the invention are selective irreversible inhibitors of Btk relative to CMET. In further or alternative embodiments, the compounds of the invention are selective irreversible inhibitors of Btk relative to EGFR. In further or alternative embodiments, the compounds of the invention are selective irreversible inhibitors of Btk relative to Lyn.

A number of animal models are useful for establishing a therapeutically effective dosage range of an irreversible Btk inhibitor compound for the treatment of any of the foregoing diseases.

For example, dosages of irreversible Btk inhibitor compounds for the treatment of autoimmune diseases can be evaluated in a mouse model of rheumatoid arthritis. In this model, arthritis was induced in Balb/c line mice by administration of anti-collagen antibody and lipopolysaccharide. See Nandakumar et al. (2003), Am. J. Pathol 163: 1827-1837.

In other examples, dosages of irreversible Btk inhibitors for the treatment of B-cell proliferative disorders can be tested, for example, in xenograft models by humans and mice, in which human B-cell lymphoma cells (e.g., Ramos cells) are implanted into immunodeficient mice (eg "nude" mice), see eg Pagel et al (2005), Clin Cancer Res 11(13):4857-4866.

Animal models for the treatment of thromboembolic diseases are also known.

The therapeutic efficacy of compounds for any of the aforementioned diseases can be optimized during the course of treatment. For example, a treated subject can undergo a diagnostic evaluation to correlate the alleviation of disease symptoms or pathology with the inhibition of Btk activity in vivo obtained by administration of a given dose of an irreversible Btk inhibitor. Cellular assays known in the art can be used to determine the in vivo activity of Btk in the presence or absence of an irreversible Btk inhibitor. For example, since activated Btk is phosphorylated at tyrosine 223 (Y223) and tyrosine 551 (Y551), phospho-specific immunocytochemical staining of P-Y223 or P-Y551-positive cells can be used to detect or Bkt activation in a cell population is quantified (eg, by FACS analysis of stained versus unstained cells). See, eg, Nisitani et al. (1999), Proc. Natl. Acad. Sci. USA 96:2221-2226. Accordingly, the amount of Btk inhibitor compound administered to a subject can be increased or decreased as necessary to maintain an optimal level of Btk inhibition for treating the disease state in the subject.

Starting materials for the synthesis of compounds described herein can be synthesized or can be obtained from commercial sources such as, but not limited to, Aldrich Chemical Co. (Milwaukee, Wisconsin), Bachem (Torrance, California), or Sigma Chemical Co. (St. Louis , Mo.). The compounds described herein, and other related compounds with different substituents, can be synthesized using techniques and starting materials known to those skilled in the art, such as described, for example, in ADVANCED ORGANIC CHEMISTRY, 4th Edition, March, (Wiley 1992); Carey and Sundberg's "ADVANCED ORGANIC CHEMISTRY", Fourth Edition, Volumes A and B (Plenum2000, 2001); Green and Wuts' "PROTECTIVE GROUPS IN ORGANIC SYNTHESIS", Third Edition, (Wiley1999); Fieser and Fieser's "Reagents for Organic Synthesis, volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, volumes 1-5 and supplements (Elsevier Science Publishers, 1989); Organic Reactions, volumes 1-40 ( John Wiley and Sons, 1991); and Larock, "Comprehensive Organic Transformations" (VCH Publishers Inc., 1989) (incorporated by reference herein in its entirety). Additional methods for the synthesis of compounds described herein can be found in International Patent Application Publication No. WO01/01982901; Arnold et al., Bioorganic & Medicinal Chemistry Letters 10 (2000) 2167-2170; Burchat et al., Bioorganic & Medicinal Chemistry Letters 12 (2002) 1687- 1690. General methods for preparing the compounds disclosed herein can be derived from reactions known in the art, and the reactions can be modified with reagents and conditions deemed appropriate by those skilled in the art to incorporate various moieties in the molecules provided herein. Synthetic methods in Examples can be used as a guide.

The reaction product can be isolated and purified, if desired, using conventional techniques including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. These products can be characterized using conventional methods, including physical constants and spectral data.

The compounds described herein can be prepared as single isomers or mixtures of isomers using the synthetic methods described herein.

The compounds described herein may possess one or more stereocenters, and each center may exist in the R or S configuration. The compounds provided herein include all diastereomeric, enantiomeric and epimeric forms, and suitable mixtures thereof. Stereoisomers may be obtained, if desired, by methods known in the art, such as separation of stereoisomers by chiral chromatographic columns.

Diastereomeric mixtures can be separated into their individual diastereoisomers on the basis of differences in physicochemical properties using known methods, for example by chromatography and/or fractional crystallization. In one embodiment, enantiomers can be separated by chiral column chromatography. In other embodiments, enantiomers may be separated by converting a mixture of enantiomers into a mixture of diastereomers by reaction with an appropriate optically active compound, such as an alcohol, to separate the diastereomers. Enantiomers and conversion (eg hydrolysis) of individual diastereomers to the corresponding pure enantiomers. All such isomers, including diastereomers, enantiomers and mixtures thereof, are considered to be part of the compositions described herein.

The methods and formulations described herein include the use of N-oxides, crystalline forms (which may also be considered polymorphs), or pharmaceutically acceptable salts of the compounds described herein, as well as active metabolites of these compounds having the same type of activity . In some cases, compounds may exist as tautomers. All tautomers are included within the scope of the compounds provided herein. Additionally, the compounds described herein can exist in pharmaceutically acceptable solvents such as water, ethanol, and the like, in both unsolvated and solvated forms. The solvated forms of the compounds presented herein are also considered disclosed herein.

By using a reducing agent such as but not limited to sulfur, sulfur dioxide, triphenylphosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, etc., at 0 ° C to 80 ° C and a suitable inert organic solvent , such as but not limited to acetonitrile, ethanol, di Prepare non-oxidized forms from N-oxides by treating them in aqueous solution of alkanes.

In some embodiments, the compounds described herein are formulated as prodrugs. "Prodrug" refers to an agent, which is converted in vivo to the parent drug. Prodrugs are often useful because, in some cases, they can be easier to administer than the parent drug. They can be bioavailable, eg by oral administration, whereas the parent drug cannot. The prodrugs may also have improved solubility in pharmaceutical compositions over the parent drug. Examples of prodrugs are, without limitation, compounds described herein that are administered as esters (the "prodrugs") to facilitate transport across cell membranes, where water solubility is not conducive to such transport, but which are then Metabolic hydrolysis to carboxylic acids, active entities, once inside cells, water solubility is beneficial. A further example of a prodrug may be a short peptide (polyamino acid) linked to an acid group, where the peptide is metabolized to reveal the active moiety. In certain embodiments, upon in vivo administration, a prodrug is chemically converted to a biologically, pharmaceutically or therapeutically active form of the compound. In certain embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to a biologically, pharmaceutically or therapeutically active form of the compound. To produce prodrugs, a pharmaceutically active compound is modified such that the active compound is regenerated when administered in vivo. The prodrugs can be designed to alter the metabolic stability or transport properties of the drug, to mask side effects or toxicity, to improve the action of the drug or to alter other properties or properties of the drug. Once a pharmaceutically active compound is known, one skilled in the art can design prodrugs of the compound based on knowledge of pharmacodynamic methods and in vivo metabolism of the drug (see, e.g., "Nogrady (1985) Medicinal Chemistry A Biochemical Approach" Oxford University Press , New York, pp. 388-392; Silverman (1992), The Organic Chemistry of Drug Design and Drug Action, Academic Press, Inc., San Diego, pp. 352-401, Saulnier et al. (1994), Bioorganic and Medicinal Chemistry Letters Vol. 4, p. 1985).

Prodrug forms of the compounds described herein, wherein said prodrugs are metabolized in vivo to give derivatives as previously described are included within the scope of the claims. In some cases, some of the compounds described herein may be other derivatives or prodrugs of active compounds.

Prodrugs are often useful because, in some cases, they can be administered more easily than the parent drug. They can be bioavailable, eg by oral administration, whereas the parent drug cannot. In pharmaceutical compositions, the prodrug may also have improved solubility relative to the parent drug. Prodrugs can be designed as reversible drug derivatives that act as modifiers to enhance drug delivery to specific site tissues. In some embodiments, the design of the prodrug increases the effective water solubility. See, eg, Fedorak et al., Am. J. Physiol, 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992) ; J.Larsen and H.Bundgaard, Iht.J.Pharmaceutics, 37, 87 (1987); J.Larsen et al., Int.J.Pharmaceutics, 47, 103 (1988); Sinkula et al., J.Pharm.Sd., 64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, the A.C.S. Symposium Series, Volume 14; and Edward B. Roche, Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, which is hereby incorporated by reference in its entirety.

The compounds described herein include isotopically labeled compounds that are equivalent to those provided herein with various molecular formulas and structures, but in fact one or more atoms, are represented by atoms having a different atomic mass or mass number than the atoms normally found in nature. replacement. Examples of isotopes that can be introduced into these compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine, such as ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ^35S , ^18F , ^36Cl . Certain isotopically labeled compounds described herein, eg, those into which radioactive isotopes, such ^{as3H and14C} , have been incorporated, can be used to determine drug and/or substrate tissue distribution. Furthermore, substitution with isotopes such as deuterium, ^ie2H , affords certain therapeutic advantages, eg increased in vivo half-life or reduced required dosage, due to greater metabolic stability.

In additional or further embodiments, the compounds described herein are administered to an organism in need thereof and metabolized within the body to produce metabolites which are then used to produce a desired effect, including a desired therapeutic effect.

The compounds described herein can be formulated and/or used as pharmaceutically acceptable salts. Types of pharmaceutically acceptable salts include, but are not limited to: (1) acid addition salts, formed by reacting the free base form of a compound with a pharmaceutically acceptable inorganic acid such as hydrochloric acid, hydrobromic acid, Sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, etc.; or formed by reaction with organic acids such as acetic acid, propionic acid, caproic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid , malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethyl Alkanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene -1-Formic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid , lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, etc.; (2) salt, when the acidic proton in the parent compound is replaced by a metal ion Formation, for example, of alkali metal ions (eg, lithium, sodium, potassium), alkaline earth metal ions (eg, magnesium or calcium), or aluminum ions; or coordination with organic bases. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, trimethylamine, N-methylglucamine, and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.

The corresponding counterions of pharmaceutically acceptable salts can be analyzed and identified using various methods including, but not limited to, ion exchange chromatography, ion chromatography, capillary electrophoresis, inductively coupled plasma, atomic absorption spectroscopy, mass spectrometry, or their derivatives. any combination.

The salt is recovered using at least one of the following techniques: filtration, precipitation with a non-solvent followed by filtration, solvent evaporation, or in the case of an aqueous solution, lyophilization.

It should be understood that references to pharmaceutically acceptable salts include solvent added forms or crystal forms thereof, especially solvates or polymorphs. Solvates contain stoichiometric or non-stoichiometric amounts of solvent and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein may be conveniently prepared or formed in the methods described herein. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.

It should be understood that references to salts include solvent added forms or crystal forms thereof, especially solvates or polymorphs. Solvates contain stoichiometric or non-stoichiometric amounts of solvent and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Polymorphs include different crystal packing arrangements of the same elemental composition of a compound. Polymorphs generally have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optical and electrical properties, stability, and solubility. Various factors such as recrystallization solvent, crystallization rate, and storage temperature can lead to a single monocrystalline form predominating.

The compounds described herein can be in various forms including, but not limited to, amorphous, spherical, and nanoparticulate forms. Additionally, the compounds described herein include crystalline forms, also known as polymorphs. Polymorphs include different crystal packing arrangements of the same elemental composition of a compound. Polymorphs generally have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optical and electrical properties, stability, and solubility. Various factors such as recrystallization solvent, crystallization rate, and storage temperature can lead to a single crystalline form predominating.

Screening and characterization of pharmaceutically acceptable salts, polymorphs and/or solvates can be accomplished using a variety of techniques including, but not limited to, thermal analysis, X-ray diffraction, spectroscopy, vapor sorption and microscopy. Thermal analysis methods focus on thermochemical degradation or thermophysical processes, including but not limited to polymorphic transformation, and these methods are used to analyze the relationship between polymorphic forms, determine the weight loss, to find the glass transition temperature, or for Excipient compatibility studies. These methods include, but are not limited to, differential scanning calorimetry (DSC), modulated differential scanning calorimetry (MDCS), thermogravimetric analysis (TGA), and thermogravimetric and infrared analysis (TG/IR). X-ray diffraction methods include, but are not limited to, single crystal and powder diffractometers and synchrotron sources. Various spectroscopic techniques were used including, but not limited to, Raman, FTIR, UVIS and NMR (liquid and solid state). Various microscopic techniques including, but not limited to, polarized light microscopy, scanning electron microscopy (SEM) and energy dispersive X-ray analysis (EDX), environmental scanning electron microscopy and EDX (under a gas or water vapor atmosphere), IR microscopy and Raman microscopy.

Throughout this specification, groups and substituents thereof can be selected by one skilled in the art to provide stable moieties and compounds.

Described herein are methods, compositions, uses and medicaments for the treatment of disorders comprising administering inhibitors of ACK to a patient in need thereof. In some embodiments, the ACK is Btk or a Btk homolog. In further embodiments, ACK is Blk or a Blk homolog. In still further embodiments, ACK is a tyrosine kinase that shares homology to Btk by having cysteine residues (including the Cys481 residue) that can form a covalent bond with an inhibitor.

The methods described herein (which include using a pharmaceutical composition to treat a disease or condition, or using a compound to form a medicament for treating a disease or condition) comprise administering to an individual in need thereof a Btk inhibitor comprising a therapeutically effective amount of one or more Btk inhibitors described herein. Composition of pharmaceutical compounds. Without being bound by theory, the differential roles played by Btk signaling in various hematopoietic cell functions such as B cell receptor activation suggest that small molecule Btk inhibitors are useful for the treatment of a variety of cells affected by or affecting a variety of hematopoietic cell types. Diseases of cell types, or reducing the risk thereof, are useful, including, for example, autoimmune diseases, heteroimmune conditions or diseases, inflammatory diseases, cancers (eg, B cell proliferative diseases), and thromboembolic disorders.

In some embodiments, is a method of treating an autoimmune disease or condition comprising administering to a patient in need thereof any of the Btk (or Pharmaceutical formulations of Btk homologues) inhibitors. Such autoimmune diseases or conditions include, but are not limited to, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, lupus, diabetes, myasthenia gravis, Hashimoto's thyroiditis , Ord's thyroiditis, Graves' disease, Sjogren's syndrome, multiple sclerosis, Guillain-Barre syndrome, acute disseminated encephalomyelitis, Addison's disease, strabismus oculoclonus-myoclonus syndrome syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, pulmonary hemorrhage and nephritic syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary Biliary cirrhosis, Reiter's syndrome, Taurus arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behcet's disease, chronic fatigue, Familial dysautonomia, endometriosis, interstitial cystitis, neuromyotonia, scleroderma, and vulvodynia. In some embodiments, the autoimmune disease is selected from rheumatoid arthritis or lupus.

In some embodiments, is a method of treating a heteroimmune disease or condition comprising administering to a patient in need thereof any of the Btk (or Pharmaceutical formulations of Btk homologues) inhibitors. Such heteroimmune conditions or diseases include, but are not limited to, graft-versus-host disease, transplantation, blood transfusions, anaphylaxis, allergic reactions (e.g., to plant pollen, latex, drugs, foods, insect poisons, animal hair, animal dander, dust mite or cockroach gill tablets), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis.

In some embodiments, is a method of treating cancer comprising administering any one of the Btk (or Btk homologues) of the compounds of the invention (e.g., the compounds described above in the first to third aspects) to a patient in need thereof Pharmaceutical preparations of inhibitors. Such cancers, such as B-cell proliferative disorders, include but are not limited to diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphocytic Plasma cell lymphoma/Walbacher's macroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, mantle cell lymphoma lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt lymphoma/leukemia, and lymphomatoid granulomatosis.

In some embodiments, it is a method of treating mastocytosis comprising administering any one of the Btk (or Btk) compounds of the invention (such as those described in the first to third aspects above) to a patient in need thereof. Homologues) inhibitors of pharmaceutical preparations. Mastocytosis includes, but is not limited to, disorders characterized by overactive mast cells.

In some embodiments, is a method of treating osteoporosis or bone resorption disorder comprising administering any of the compounds of the invention (e.g., the compounds described above in the first to third aspects) to a patient in need thereof Pharmaceutical formulations of Btk (or Btk homolog) inhibitors. Disorders of bone resorption include, but are not limited to, Paget's disease of the bone, osteoporosis, and bone changes secondary to cancer, such as occurs in myeloma and metastases from breast cancer.

In some embodiments, is a method of treating an inflammatory disease comprising administering any one of the Btk (or Btk homologous) compounds of the invention (e.g., the compounds described in the first to third aspects above) to a patient in need thereof Drug preparations of inhibitors. Inflammatory diseases include, but are not limited to, asthma, inflammatory bowel disease, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, lacrimal glanditis , dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrous tissue inflammation, gastritis, gastroenteritis, hepatitis, suppuration Hidradenitis, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleurisy, Phlebitis, pneumonia, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, and Vulvitis.

In some embodiments, is a method of treating a thromboembolic disease comprising administering any one of the Btk (or Btk homologues) of the compounds of the invention (such as those described in the first to third aspects above) to a patient in need thereof Drug preparations of inhibitors. Thromboembolic disease including but not limited to myocardial infarction, angina (including unstable angina), reocclusion or restenosis after angioplasty or aortocoronary bypass, stroke, transient ischemia, peripheral arterial occlusive disease , pulmonary embolism and deep vein thrombosis.

In addition, the Btk inhibitor compounds described herein can be used to inhibit a small subset of other tyrosine kinases by having cysteine residues (including Cys481 residues) that can form covalent bonds with the inhibitors. base), which has homology with Btk. Accordingly, a subset of tyrosine kinases other than Btk are also expected to be useful therapeutic targets in a number of health conditions, including:

Autoimmune diseases, including but not limited to rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, lupus, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord 's thyroiditis, Graves' disease, Sjogren's syndrome, multiple sclerosis, Guillain-Barre syndrome, acute disseminated encephalomyelitis, Addison's disease, strabismus oculoclonus-myoclonus syndrome, Ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, pulmonary hemorrhage nephritic syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary Cirrhosis, Reiter's Syndrome, Taurus Arteritis, Temporal Arteritis, Warm Autoimmune Hemolytic Anemia, Wegener's Granulomatosis, Psoriasis, Alopecia Universalis, Behcet's Syndrome, Chronic Fatigue, Familial Dysautonomia, endometriosis, interstitial cystitis, neuromyotonia, scleroderma, and vulvodynia.

· Heteroimmune conditions or diseases, including but not limited to graft-versus-host disease, transplantation, blood transfusion, anaphylaxis, allergic reactions (e.g., to plant pollen, latex, drugs, food, insect poisons, animal hair, animal dander, dust mite or cockroach gill tablets), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis.

Inflammatory diseases, including but not limited to asthma, inflammatory bowel disease, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, Lacrimal gland inflammation, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrous tissue inflammation, gastritis, gastroenteritis, hepatitis , hidradenitis suppurativa, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, Pleurisy, phlebitis, local pneumonia, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, uveitis, vaginitis, blood vessels Inflammation and vulvitis.

Cancers, such as B-cell proliferative disorders, which include, but are not limited to, diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphocytic Plasma cell lymphoma/Walbacher's macroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, mantle cell lymphoma lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt lymphoma/leukemia, and lymphomatoid granulomatosis.

Thromboembolic disorders, including but not limited to myocardial infarction, angina (including unstable angina), reocclusion or restenosis after angioplasty or aortocoronary bypass, stroke, transient ischemia, peripheral arterial occlusive disorder , pulmonary embolism and deep vein thrombosis.

• Mastocytosis, including but not limited to disorders characterized by hyperactive mast cells.

Disorders of bone resorption, including but not limited to Paget's disease of the bone, osteoporosis, and bone changes secondary to cancer, such as arises in myeloma and metastasis from breast cancer.

Symptoms, diagnostic tests, and prognostic tests for each of the above conditions include, for example, "Harrison's Principles of Internal ", 16th edition, 2004, The McGraw-Hill Companies, Inc. Dey et al., (2006), Cytojournal3(24) and "Revised European American Lymphoma" (REAL)) classification system (see Such as the website maintained by the National Cancer Institute).

A number of animal models are useful for establishing therapeutically effective dosage ranges for inhibitors, including Btk inhibitor compounds, to treat any of the foregoing diseases. Likewise, for example, doses of inhibitor compounds for the treatment of autoimmune diseases can be assessed in a mouse model of rheumatoid arthritis. In this model, arthritis is induced in Balb/c mice by administration of anti-collagen antibodies and lipopolysaccharide. See Nandakumar et al., (2003), Am. J. Pathol 163: 1827-1837. In another example, doses of inhibitors for the treatment of B-cell proliferative disorders can be tested, for example, in a human-to-mouse xenograft model in which human B-cell lymphoma cells (eg, Ramos cells) are implanted into immune In deficient mice (eg "nude" mice), as described eg in Pagel et al. (2005), Clin Cancer Res 11(13):4857-4866. Animal models for the treatment of thromboembolic disorders are also known.

In one embodiment, the therapeutic efficacy of the compound against one of the aforementioned diseases is optimized during the course of treatment. For example, the treated individual optionally undergoes a diagnostic evaluation to correlate amelioration of disease symptoms or pathology with inhibition of Btk activity in vivo achieved by administration of the indicated dose of the Btk inhibitor. Cellular assays are used to determine the in vivo activity of Btk in the presence or absence of Btk inhibitors. For example, because activated Btk is phosphorylated at tyrosine 223 (Y223) and tyrosine 551 (Y551), phospho-specific immunocytochemical staining of P-Y223 or P Y551-positive cells was used to detect or quantify Activation of Bkt in cell populations (eg, by FACS analysis comparing stained/unstained cells). See, eg, Nisitani et al., (1999), Proc. Natl. Acad. Sci, USA 96:2221-2226. Accordingly, the amount of Btk inhibitor compound administered to an individual is optionally increased or decreased as necessary in order to maintain the level of Btk inhibition optimal for treating the individual's disease state.

In another aspect, are methods of modulating (including irreversibly inhibiting) the activity of Btk or other tyrosine kinases, wherein the other tyrosine kinases are obtained by having a half-body capable of forming a covalent bond with at least one irreversible inhibitor described herein. Cystine residues (including Cys481 residues), having homology with Btk, in mammals, at least one of the above-mentioned first to third aspects (preferably second, Three aspects, more preferably the compound of any structure in the third aspect). On the other hand, it is a method for regulating (including irreversibly inhibiting) Btk activity in mammals, comprising administering at least once an effective amount of at least one of the above-mentioned first to third aspects (preferably second and third aspects, Compounds of any structure in the third aspect) are more preferred. In another aspect, it is a method for treating a Btk-dependent or Btk-mediated condition or disease, comprising administering at least one effective amount of at least one of the above-mentioned first to third aspects (preferably second, third, and more) to a mammal at least once. Compounds of any structure in the third aspect) are preferred.

In one embodiment, an irreversible Btk inhibitor compound selectively and irreversibly inhibits the activated form of its target tyrosine kinase (eg, the phosphorylated form of the tyrosine kinase). For example, activated Btk is transphosphorylated at tyrosine 551. Thus, in these embodiments, an irreversible Btk inhibitor inhibits a target kinase in a cell only when the target kinase is activated by a signaling event. For example, compounds of the invention are capable of modulating/inhibiting phosphorylation of Tyr551 and/or Tyr223 residues of Btk.

Typically, irreversible inhibitor compounds used in the methods described herein are identified or characterized in in vitro assays, such as cell-free biochemical assays or cellular functional assays. Such assays are useful for determining the in vitro IC50 of irreversible inhibitor compounds.

For example, in some embodiments, a cell-free kinase assay is used to measure kinase activity following incubation of the kinase in the absence or presence of a range of concentrations of a candidate inhibitor compound. If the candidate compound is in fact an inhibitor, repeated washes with inhibitor-free medium will not restore kinase activity. See, eg, J.B. Smaill et al. (1999), J. Med. Chem. 42(10):1803-1815. Furthermore, the formation of a covalent complex between a kinase and a candidate inhibitor is a useful indicator of kinase inhibition, which can be readily determined by a number of methods, such as mass spectrometry.

In some embodiments, the inhibitors described herein are used in the manufacture of a therapeutic for any of the foregoing conditions (eg, autoimmune disease, inflammatory disease, allergic disorder, B cell proliferative disorder, or thromboembolic disorder).

In one embodiment, an inhibitor compound selectively inhibits the activated form of its target tyrosine kinase (eg, the phosphorylated form of the tyrosine kinase). For example, activated Btk is transphosphorylated at tyrosine 551. Thus, in these embodiments, the Btk inhibitor inhibits the target kinase in the cell only when the target kinase is activated by a signaling event. For example, compounds of the invention are capable of modulating/methylating the phosphorylation of Tyr551 and/or Tyr223 residues of Btk.

In a further embodiment, the compounds of the invention irreversibly inhibit Btk and are used to treat patients with a Bruton's tyrosine kinase-dependent or Bruton's tyrosine kinase-mediated condition or disease that Or diseases include but are not limited to cancer, autoimmune and other inflammatory diseases.

combination therapy

The Btk inhibitor compositions described herein may also be used in combination with other well known therapeutic agents selected for their therapeutic value to the condition being treated. In general, the compositions described herein, in embodiments using combination therapy, and the other agents need not be administered in the same pharmaceutical composition, and optionally must be administered by different routes because of different physical and chemical characteristics. For example, initial administration is carried out according to an established regimen, and the dosage, mode of administration and frequency of administration are then modified based on the observed effect.

In certain instances, it may be appropriate to administer at least one Btk inhibitor compound described herein in combination with another therapeutic agent. By way of example only, if nausea is one of the side effects experienced by a patient receiving one of the Btk inhibitor compounds described herein, then the administration of an anti-nausea agent in combination with the initial therapeutic agent may be appropriate. Alternatively, by way of example only, the therapeutic effectiveness of one of the compounds described herein is enhanced by the administration of an adjuvant (i.e., the adjuvant itself has minimal therapeutic benefit, but when combined with another therapeutic agent contributes significantly to the overall therapeutic benefit of the patient). benefits are enhanced). Alternatively, by way of example only, by administering a compound described herein and another therapeutic agent (also including a treatment regimen) that also has a therapeutic benefit, the patient experiences an increased benefit. Regardless, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient is, in some embodiments, simply additive of the two therapeutic agents, or in other embodiments, the patient experiences a synergistic benefit.

The particular choice of compound to be employed will depend upon the diagnosis and judgment of the attending physician regarding the patient's condition and appropriate treatment regimen. The compounds are optionally administered simultaneously (eg, simultaneously, substantially simultaneously, or within the same treatment regimen) or sequentially, depending on the nature of the disease, disorder or condition, the condition of the patient, and the actual choice of compounds used. During a treatment regimen, the order of administration and the number of repeated administrations of each therapeutic agent is determined based on the disease being treated and an assessment of the patient's condition.

Therapeutically effective doses can vary when the drugs are used in therapeutic combinations. Methods for experimentally determining therapeutically effective doses of drugs and other agents used in combination treatment regimens are described in the literature. For example, the use of metronomic dosing to deliver more frequent, lower doses with the goal of minimizing toxic side effects has been widely described in the literature. Combination therapy further includes periodic therapy that is started and stopped at different times to aid in the clinical management of the patient.

For the combination therapies described herein, dosages of the co-administered compounds will of course vary depending upon the type of co-drug employed, the particular drug employed, the disease or condition being treated, and the like. Additionally, when co-administered with one or more biologically active agents, the compounds provided herein can be administered concurrently or sequentially with the biologically active agents. If administered sequentially, the attending physician will determine the appropriate sequence of administering the proteins in combination with the biologically active agents.

Regardless, the multiple therapeutic agents, one of which is a compound of the invention (such as the compounds described above in the first to third aspects), are optionally administered in any order or even simultaneously. If administered simultaneously, the multiple therapeutic agents are optionally provided in a single integrated form, or in multiple forms (by way of example only, as a single pill or as two separate pills). One therapeutic agent may be given in multiple doses, or both may be given as multiple doses. If not administered simultaneously, the time between doses can vary from more than zero weeks to less than four weeks. In addition, combination methods, compositions and formulations are not limited to the use of only two agents; the use of multiple therapeutic combinations is also contemplated.

It will be appreciated that dosage regimens for treating, preventing or ameliorating the condition for which relief is sought may be modified according to a number of factors. These factors include the condition the individual has, as well as the individual's age, weight, sex, diet and medical condition. Thus, the dosage regimen actually employed can vary widely and can thus deviate from the dosage regimen set forth herein.

The agents making up the combination therapy disclosed herein may be in combined dosage form, or in separate dosage forms intended to be administered substantially simultaneously. The agents making up the combination therapy may also be administered sequentially, with either therapeutic compound being administered by a regimen requiring two-step administration. A two-step administration regimen may require sequential administration of the active agents, or spaced administration of separate active agents. The period of time between administration steps can vary from minutes to hours, depending on properties of the individual agent, such as potency, solubility, bioavailability, plasma half-life, and kinetic characteristics of the agent. Circadian changes in the concentration of the target molecule can also determine optimal dosage intervals.

In addition, the compounds described herein are also optionally used in conjunction with procedures that provide additional or synergistic benefits to the patient. By way of example only, patients are expected to find therapeutic and/or prophylactic benefit in the methods described herein in which pharmaceutical compositions of the compounds disclosed herein and/or in combination with other therapeutic agents are combined with genetic testing to determine whether an individual Are carriers of mutated genes known to be associated with certain diseases or conditions.

In some embodiments, the compounds described herein and combination therapies are administered before, during, or after the onset of a disease or condition, and the timing of administration of compositions comprising the compounds can vary. Thus, for example, a compound may be used as a prophylactic and may be administered continuously to an individual predisposed to developing a condition or disease with the aim of preventing the occurrence of the disease or condition. Compounds and compositions can be administered to the individual during the onset of symptoms, or as soon as possible after the onset of symptoms. Administration of the compound can begin within the first 48 hours of symptom onset, within the first 6 hours of symptom onset, or within 3 hours of symptom onset. The initial administration can be by any practical route, such as intravenous injection, bolus injection, infusion over 5 minutes to about 5 hours, pill, capsule, transdermal patch, buccal delivery, etc., or combinations thereof. The compounds should be administered within the shortest time practicable after the onset of a disease or condition is detected or suspected, and for the period of time necessary to treat the disease, eg, about 1 month to about 3 months. The length of treatment can vary for each individual, and the length can be determined using known criteria. For example, a compound or a formulation comprising the compound can be administered for at least 2 weeks, from about 1 month to about 5 years, or from about 1 month to about 3 years.

EXEMPLARY THERAPEUTIC AGENTS USED IN COMBINATION WITH INHIBITOR COMPOUNDS

In some embodiments, when an individual has or is at risk of having an autoimmune disease, an inflammatory disease, or an allergic disease, a Btk inhibitor compound is used in any combination with one or more of the following therapeutic agents: immunosuppressants ( eg tacrolimus, cyclosporine, rapamycin, methotrexate, cyclophosphamide, azathioprine, mercaptopurine, mycophenolate mofetil, or FTY720), corticosteroids (eg, prednisone, acetate Cortisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclomethasone, fludrocortisone acetate, deoxycorticosterone acetate, aldosterone), NSAIDs (such as salicylates, arylalkanoic acids, 2-arylpropionic acids, N-arylanthranilic acids, oxicams, coxibs, or sulfanilines), Cox-2-specific inhibitors ( eg valdecoxib, celecoxib, or rofecoxib), leflunomide, aurothioglucose, gold thiomalate, aurofin, sulfasalazine, hydroxychloroquine, minocycline, TNF-alpha Binding proteins (eg, infliximab, etanercept, or adalimumab), abatacept, anakinra, interferon-beta, interferon-gamma, interleukin-2, allergy vaccines, Antihistamines, antileukotrienes, beta-agonists, theophylline, anticholinergics, or other selective kinase inhibitors (eg, p38 inhibitors, Syk inhibitors, PKC inhibitors).

In yet other embodiments, any combination of a Btk inhibitor compound and one or more other anticancer agents is administered when the individual has or is at risk of having a B-cell proliferative disorder (e.g., plasma cell myeloma). The individual is treated in combination. In some embodiments, one or more anticancer agents are pro-apoptotic agents. Examples of anticancer agents include, but are not limited to, any of the following: gossypol, genasense, polyphenol E, chlorofusin, all-trans retinoic acid (ATRA), bryostatin, tumor necrosis factor-associated apoptosis Inducible ligand (TRAIL), 5-aza-2'-deoxycytidine, all-trans retinoic acid, doxorubicin, vincristine, etoposide, gemcitabine, imatinib Geldanamycin, 17-N-allylamino-17-desmethoxygeldanamycin (17AAG), Flapindus, LY294002, Bortezomib, Trastuzumab, BAY11-7082, PKC412 or PD184352, Taxol ^™ , also known as "paclitaxel", is a well known anticancer drug that acts by enhancing and stabilizing microtubule formation, and analogs of Taxol ^™ such as Taxotere ^™ . Compounds with an essential taxane backbone as a common structural feature have also been shown to have the ability to arrest cells in the G2-M phase due to the stabilization of microtubules, and may be useful in combination with the compounds described herein for the treatment of cancer.

Further examples of anticancer agents used in combination with Btk inhibitor compounds include inhibitors of mitogen-activated protein kinase signaling, such as U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY43-9006, wortmannin or LY294002; Syk inhibitors; mTOR inhibitors; and antibodies (eg, rituxan).

In further embodiments, other anticancer agents used in combination with Btk inhibitor compounds include doxorubicin, actinomycin D, bleomycin, vinblastine, cisplatin, acevectin; arubicin ; Alcodazole hydrochloride; Acronine; Adorexine; Aldesleukin; Hexamethylmelamine; Asparaginase; trilinactin; azacitidine; azatepa; azomycin; batimastat; benzotepa; bicalutamide; bisantrene hydrochloride; dimethanesulfonic acid Dinaphage; Bizelexin; Bleomycin Sulfate; Buquina Sodium; Bropirilamine; Busulfan; Actinomycin C; Captestosterone; Katamide; Carbetim; Platinum; carmustine; carrubicin hydrochloride; carzelexine; sildifenagore; chlorambucil; siromycin; cladribine; clinatosulfonate; cyclophosphamide Cytidine; Dacarbazine; Daunorubicin Hydrochloride; Decitabine; Dexomaplatin; Dezaguanine; Dizaguanine Mesylate; ; Droloxifene; Droloxifene Citrate; Drostansterone Propionate; Dazocycin; ; Epilipridine; Epirubicin Hydrochloride; Eblozole; Esorubicin Hydrochloride; Estramustine; Estramustine Sodium Phosphate; Etanidazole; Etoposide; Etoposide Phosphate; Chlorine Phenytocilamine; Fadrozole Hydrochloride; Fazarabine; Fenretinide; Fluoxuridine; Fludarabine Phosphate; Fluorouracil; Flucitabine; ; hydroxyurea; idarubicin hydrochloride; ifosfamide; imofosine; interleukin II (including recombinant interleukin II or rIL2), interferon alpha-2a; interferon alpha-2b; interferon α-n1; Interferon α-n3; Interferon β-la; Interferon γ-lb; Isoproplatin; Irinotecan Hydrochloride; Lanreotide Acetate; Letrozole; Leuprolide Acetate; ; Lometrexol sodium; Lomustine; Loxoanthraquinone hydrochloride; Masoprofen; Maytansine; Nitrogen mustard hydrochloride; Er; Mercaptopurine; Methotrexate; Methotrexate Sodium; Mytomycin; Mitomectin; Mitotane; Mitoxantrone Hydrochloride; Mycophenolic Acid; Nocodazole; Noramycin; Omaplatin; Oxysulam; Pegaspargase; Perry Mycin; Pentamethine; Pelomycin Sulfate; Pephosfamide; Piperbromide; Piposufan; Piroxantrone Hydrochloride; Mycin; Prednimustine; Procarbazine hydrochloride; Puromycin; Puromycin hydrochloride; Semustine; octrazine; sodium phosphoacetylaspartate; spamycin; germanospiramine hydrochloride; spiromustine; spiroplatinum; Limycin; Tecogalan Sodium; Tegafur; Tiloxantrone Hydrochloride; Temoporfin; Teniposide; Tiroxiron; Testolactone; Thiametine thioguanine; thiotepa; thiazofurin; tirapazamine; toremifene citrate; Triptorelin; Tobrazole Hydrochloride; Ulamustine; Uretepa; Vapreotide; Verteporfin; Vinblastine Sulfate; Vincristine Sulfate; Vindesine; Vindesine Sulfate; Vinblastine Sulfate Pidine; Vinblastine Sulfate; Vinblastine Sulfate; Vinorelbine Tartrate; Vinblastine Sulfate;

In yet other embodiments, other anticancer agents used in combination with Btk inhibitor compounds include: 20-epi-1,25-dihydroxyvitamin D3; 5-ethynyluracil; Abiraterone; Arubicin ; acylfulvene; adenol; adolaisine; aldesleukin; ALL-TK antagonist; hexamethylmelamine; amustine; 2,4 dichlorophenoxyacetic acid; amifostine; aminoketopentane Acid; Amrubicin; Amsacrine; Anagrelide; Anastrozole; Andrographolide; Angiogenesis Inhibitor; Antagonist D; Antagonist G; Anrelix; Antidorsification Morphogenetic Protein-1; Antiandrogen, Prostate Cancer; Antiestrogens; Antineoplasticones; Antisense Oligonucleotides; ; Arginine deaminase; 9-[2-methoxy-4-(methylsulfonylamino)phenylamino]-N,5-dimethyl-4-acridinecarboxamide (asulacrine); Talestane; Amustine; Axinastatin1; Axinastatin2; Axinastatin3; Azasetron; Azatoxin; Diazotyrosine; Baccatin III Derivatives; Balano1; Batimastat; BCR/ABL antagonists; benzochlorophylls; benzoyl staurosporine; β-lactam derivatives; β-alethine; beta clarithromycin (betaclamycin) B; betulinic acid; bFGF inhibitors; Amine; Buthionine sulfoxide amine; Calcipotriol; Calphostin C; Camptothecin derivatives; Canarypox IL-2; Capecitabine; Formamide-amino-triazole; Carboxyl Amidotriazole; CaRest M3; CARN700; cartilage-derived inhibitors; kazelexin; casein kinase inhibitor (ICOS); castanospermine; cecropin B; cetrorelix; chlorophylls; sulfachloroquine Oxaline; Cicaprost; Cis-porphyrin; Cladribine; Clomiphene analogs; Clotrimazole; Collismycin A; Colistin B; Combretastatin A4; Butatin analogs; conagenin; crambescidin816; clinato; nostoc cyclic peptide 8; nostoc cyclic peptide A derivatives; curacin A; cyclopentanthraquinone; cycloplatam; cypemycin ; cytarabine sodium stearyl phosphate; cell lysing factor; hexestrol phosphate; dacisimab; decitabine; dehydrodidemnin B; Dexamethasone; Dexifosfamide; Dexrazoxane; Dexverapamil; Spermine; Dihydro-5-azacytidine; 9-Diazomycin; Diphenylspiromustine; Docosanol; Dolasetron; Doxifluridine; Droloxifene; Dronabinol; duocarmycin (duocarmycin) SA; ebselen; ecomustine; Ruubicin; Eprelide; Estramustine analogues; Estrogen agonists; Estrogen antagonists; Etanidazole; Etoposide Phosphate; Exemestane; Fadrozole; Fazarabine; Fenretinide; Filgrastim; Finasteride; Flapindus; Fluorastine; Fluorescein; Fludarabine; Fludaunomycin Hydrochloride; Forfenex; Formestane; Forsi Quxing; Formustine; Gadolinium Dexapheniramine; Gallium Nitrate; Galocitabine; Ganirelix; Gelatinase Inhibitors; Gemcitabine; Glutathione Inhibitors; Sulfamic Acid 1,7 Heptane Diyl ester (hepsulfam); cell growth factor (heregulin); hexamethylene diacetamide; hypericin; ibandronic acid; idarubicin; edoxifene; New; ilomastat; imidazoacridone; imiquimod; immunostimulatory peptide; insulin-like growth factor-1 receptor inhibitor; interferon agonist; interferon; interleukin; iodobenzguanidine; Iodoxorubicin; Sweet potato alcohol, 4-; Ilopraz; Isoladine; Isobengazole; Isohomohalicondrin B; Itasetron; F (kahalalide F); spirulina triacetate-N; lanreotide; leinamycin; legrastim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibitory factor; Leuprolide + estrogen + progesterone; leuprolide; levamisole; riazol; linear polyamine analogs; lipophilic diglycopeptide; lipophilic platinum compound; lissoclinamide7; lobaplatin; Traxol; Lonidamine; Loxoanthraquinone; Lovastatin; Loxoribine; Letotecan; ); cleavage peptide; maytansine; mannostatin A (mannostatin A); marimastatin; masorol; mammary gland serine protease inhibitory protein (maspin); Menoril; Mebalone; Metirelin; Methionase; Metoclopramide; MIF inhibitors; Mifepristone; Miltefosine; Milistim; Mismatched double strand RNA; Mitoguanidine hydrazone; Dibromodulcitol; Mitomycin analogs; Mitonaphthin; mitotoxin fibroblast growth factor-saporin; Mitoxantrone; ; monoclonal antibody, human chorionic gonadotropin; monophosphoryl lipid A + mycobacterial cell wall sk; Inhibitor 1 therapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetylgenaline; N-substituted benzamide; Neo; napavin; naphthalenediol; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; a Nitric oxide modulators; nitroxide antioxidants; nitrullyn; O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; diclofenamide ( oracin); oral cytokine inducer; omaplatin; oxatron; oxaliplatin; oxaunomycin; Panomifene; hexacoordinated catechin iron chelator parabactin (parabactin); parjeptin; pegaspargase; pedexin; pentosan polysulfate sodium; pentostatin; tray pentrozole; penfluron; pefosfamide; perillyl alcohol; phenazinomycin; phenyl acetate; phosphatase inhibitors; bisibanib; pilocarpine hydrochloride; pirarubicin ; Pitrexine; Placetin A; Placetin B; Inhibitors of Plasminogen Activators; Platinum Complexes; Platinum Compounds; Platinum-Triamine Complexes; Porfimer Sodium; Porfimycin; Prednisone; Propyl bis-acridone; prostaglandin J2; proteasome inhibitor; protein A-based immunomodulator; protein kinase C inhibitor; protein kinase C inhibitor, microalgae; protein tyrosine phosphatase inhibitor; purine Nucleoside phosphorylase inhibitors; hydroxylizarin; pyrazolinacridine; pyridoxine hydroxyethylated hemoglobin polyoxyethylene conjugates; raf antagonists; raltitrexed; ramosetron; ras farnesyl Protein transferase inhibitors; ras inhibitors; ras-GAP inhibitors; desmethyl reteptine; etidronate rhenium Re186; ememetine; romotide; roquinex; rubiginone B1; ruboxyl; safingo; saintopin; SarCNU; sarcophytol A; Inhibitor 1; sense oligonucleotide; signal transduction inhibitor; signal transduction regulator; single-chain antigen-binding protein; sizoran; Binding protein; sonamin; phosphoaspartic acid; spicamycin D; spiromustine; spleen pentapeptide; CD-spiroketal precursor δ-lactone 1; squalamine; stem cell inhibition agent; inhibitor of stem cell division; stipiamide; stromelysin inhibitor; sulfinosine; potent vasoactive intestinal peptide antagonist; s uradista; suramin; swainsonine; synthetic glycosaminoglycans; tamustine; tamoxifen mediodide; tauromustine; tazarotene; ticogalan sodium; tega Fluorine; tellurapyrylium; telomerase inhibitor; temoporfin; temozolomide; teniposide; tetrachloride decaoxide; tetrazomine; Mimetic; Thymofasin; Thymopoietin receptor agonist; Thymotrinan; Thyrotropin; Ethylpurpurin; Tirapazamine; Dichlorotitanene; ; Translation Inhibitor; Retinoic Acid; Triacetyl Uridine; Triciribine; Trimethrexate; Triptorelin; Tropisetron; Torosteride; Tyrosine Kinase Inhibitor; Tyrosine Phosphorylation Inhibitors (tyrphostins); UBC inhibitors; ubenimex; growth inhibitors of urogenital sinus origin; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; Veratramine; verdins; verteporfin; vinorelbine; vinpofostin; vitaxin; vorozole; zanotron; zeniplatin; ester.

Still other anticancer agents that may be used in combination with Btk inhibitor compounds include alkylating agents, antimetabolites, natural products or hormones such as nitrogen mustards (e.g. nitrogen mustards, cyclophosphamide, chlorambucil, etc.), Alkyl sulfonates (eg busulfan), nitrosoureas (eg carmustine, lomustine, etc.) or triazenes (dazepines, etc.). Examples of antimetabolites include, but are not limited to, folate analogs (eg methotrexate), or pyrimidine analogs (eg cytarabine), purine analogs (eg mercaptopurine, thioguanine, pentostatin).

Still other anticancer agents that can be used in combination with Btk inhibitor compounds include anti-CD20 (such as rituximab (rituximab), ocrelizumab, ofatumumab), anti-CD68 and other antibody drugs.

Examples of natural products useful in combination with Btk inhibitor compounds include, but are not limited to, vinca alkaloids (e.g., vinblastine, vincristine), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., Daunorubicin, doxorubicin, bleomycin), enzymes (eg L-asparaginase) or biological response modifiers (eg interferon alpha).

Examples of alkylating agents used in combination with Btk inhibitor compounds, in some embodiments, include, but are not limited to, nitrogen mustards (e.g., nitrogen mustards, cyclophosphamide, chlorambucil, melphalan, etc.), ethyleneimines and methylmelamines (e.g. hexamethylmelamine, thiotepa), alkyl sulfonates (e.g. busulfan), nitrosoureas (e.g. carmustine, lomustine, semustine, chain Zoxin, etc.) or triazene (damine, etc.). Examples of antimetabolites include, but are not limited to, folic acid analogs (e.g. methotrexate), or pyrimidine analogs (e.g. fluorouracil, floxuridine, cytarabine), purine analogs (e.g. mercaptopurine, thioguanine, Pentostatin).

Examples of hormones and antagonists useful in combination with Btk inhibitor compounds include, but are not limited to, corticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, megestrol acetate, progesterone), estrogens (e.g., diethylstilbestrol, ethinylestradiol), antiestrogens (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogens (e.g., flutamide), progesterone Gonadal hormone-releasing hormone analogs (eg, leuprolide). Other agents that can be used in the methods and compositions described herein to treat or prevent cancer include platinum coordination complexes (e.g., cisplatin, carboplatin), anthraquinones (e.g., mitoxantrone), substituted ureas (e.g., Hydroxyurea), methylhydrazine derivatives (such as procarbazine), adrenocortical inhibitors (such as mitotane, aminoglutethimide).

Anticancer agents that act by arresting cells in the G2-M phase due to stabilization of microtubules, and in some embodiments are used in combination with Btk inhibitor compounds, examples of which include without limitation marketed drugs and in development medicine.

When an individual has or is at risk of having a thromboembolic disorder (eg, stroke), in some embodiments, the individual is treated with any combination of a Btk inhibitor compound and one or more other antithromboembolic agents. Examples of antithromboembolic agents include, but are not limited to, any of the following: thrombolytic agents (such as alteplase, anistreplase, streptokinase, urokinase, or tissue plasminogen activator), heparin, tinzaparin , warfarin, dabigatran (such as dabigatran etexilate), factor Xa inhibitors (such as fondaparinux, draparinux, rivaroxaban, DX-9065a, omixaban, LY517717 or YM150), factor VIIa inhibitors, ticlopidine, clopidogrel, CS-747 (prasugrel, LY640315), ximelagatran, or BIBR1048.

Pharmaceutical Composition/Preparation

Pharmaceutical compositions are formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent on the route of administration chosen. The pharmaceutical compositions described herein are summarized in, for example, Remington: The Science and Practice of Pharmacy, Nineteenth Edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L. eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Edition (Lippincott Williams & Wilkins 1999).

The pharmaceutical composition used herein refers to the compounds of the present invention (such as the compounds described in the first to third aspects above), together with other chemical components such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners and/or mixtures of excipients. Pharmaceutical compositions facilitate the administration of a compound to an organism. In practicing the methods of treatment or uses provided herein, a therapeutically effective amount of a compound described herein is administered in a pharmaceutical composition to a mammal suffering from the disease, disorder or condition to be treated. Preferably, the mammal is a human. The compounds are used in some embodiments alone or in combination with one or more therapeutic agents as components of a mixture.

The pharmaceutical formulations described herein are, in some embodiments, administered to an individual by a variety of routes of administration, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration way. The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate-release formulations, controlled-release formulations, fast-dissolving formulations, tablets, Capsules, pills, delayed release formulations, extended release formulations, pulsed release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.

Pharmaceutical compositions comprising compounds described herein are optionally prepared in a conventional manner, such as, by way of example only, by conventional mixing, dissolving, granulating, dragee-coating, levigating, emulsifying, encapsulating, entrapping or compression processes means.

In a further embodiment, the pharmaceutical composition comprises at least one compound described herein, such as the compound described in the first to third aspects above, in free acid or free base form, or as a pharmaceutically acceptable salt form as the active ingredient. In addition, the methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms (also known as polymorphs) and active metabolites of these compounds having the same type of activity. In some cases, compounds exist as tautomers. All tautomers are included within the scope of the compounds presented herein.

In addition, the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.

"Carrier" or "carrier material" includes excipients in pharmaceuticals and is based on compatibility with the compounds of the present invention (such as the compounds described above in the first to third aspects) and the release characteristics of the desired dosage form. And choose. Exemplary carrier materials include, for example, binders, suspending agents, disintegrants, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, and the like. See, e.g., Remington: The Science and Practice of Pharmacy, Nineteenth Edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L. eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Edition (Lippincott Williams & Wilkins 1999).

"Measurable serum concentration" or "measurable plasma concentration" describes serum or plasma concentration, typically measured in mg, μg, or ng of therapeutic agent per ml, dl, or l of serum absorbed into the bloodstream after administration . As used herein, measurable plasma concentrations are typically measured in ng/ml or μg/ml.

"Pharmacokinetics" refers to the factors that determine the biological response observed at the site of action relative to drug concentration. "Pharmacokinetics" refers to the factors that determine the achievement and maintenance of appropriate drug concentrations at the site of action.

As used herein, "steady state" is when the amount of drug administered equals the amount of drug eliminated within a dosing interval resulting in a plateau or constant plasma drug exposure.

dosage form

Furthermore, pharmaceutical compositions described herein comprising compounds of the invention (eg, compounds described in the first to third aspects above) are, in some embodiments, formulated in any suitable dosage form, including but not limited to aqueous oral Dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, etc., for oral ingestion by patients to be treated, solid oral dosage forms, aerosols, controlled-release preparations, fast-dissolving preparations, effervescent preparations, freeze-dried Formulations, tablets, powders, pills, dragees, capsules, delayed release formulations, sustained release formulations, pulsed release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.

Pharmaceutical solid dosage forms described herein, optionally comprising a compound described herein and one or more pharmaceutically acceptable additives, such as compatible carriers, binders, fillers, suspending agents, flavoring agents, sweeteners , disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, wetting agents, plasticizers, stabilizers, penetration enhancers, wetting agents, antifoaming agents, antioxidants, anticorrosion agents, or one or more combinations thereof. In yet other aspects, compounds of the invention (e.g., compounds described above in the first to third aspects) are surrounded using standard coating procedures, such as those described in Remington's Pharmaceutical Sciences, 20th Edition (2000). ) formulations to provide a film coating. In one embodiment some or all of the particles of a compound of the invention (such as a compound described above in the first to third aspects) are coated. In another embodiment, some or all of the particles of a compound of the invention (such as a compound described in the first to third aspects above) are microencapsulated. In yet another embodiment, the particles of the compound of the invention (such as those described above in the first to third aspects) are neither microencapsulated nor coated.

Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipients with one or more compounds described herein, optionally grinding a resulting mixture, and after adding suitable auxiliaries, if desired The mixture of granules is processed to obtain tablets or dragee cores. Suitable excipients include, for example, fillers, such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl Cellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others, such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If desired, disintegrants may be added, such as cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbomer gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvent or solvent mixture. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.

In some embodiments, the solid dosage forms disclosed herein can be in the form of tablets (including suspension tablets, fast-dissolving tablets, chewable disintegrating tablets, rapidly disintegrating tablets, effervescent tablets or caplets), pills, powders (including sterile packaged powders, dispensable powders, or effervescent powders), capsules (including soft or hard capsules, such as those made from gelatin of animal origin or HPMC of vegetable origin, or "sprinkle capsules"), solid Dispersion, solid solution, bioerodible, controlled release, pulsed release, multiparticulate, pellet, granule or aerosol form. In other embodiments, the pharmaceutical formulation is in powder form. In still other embodiments, the pharmaceutical formulation is in the form of a tablet, including but not limited to a fast-dissolving tablet. Furthermore, the pharmaceutical formulations described herein may be administered as single capsule or multi-capsule dosage forms. In some embodiments, the pharmaceutical formulation is administered in two or three or four capsules or tablets.

In some embodiments, solid dosage forms such as tablets, effervescent tablets and capsules are obtained by combining granules of the compound of the present invention (such as the compound described in the first to third aspects above) with one or more pharmaceutical excipients. Formulations are mixed to form bulk blend compositions. When these bulk blend compositions are referred to as homogeneous, it is meant that particles of the compounds of the invention (such as those described above in the first to third aspects) are uniformly dispersed throughout the composition such that the composition Can be easily subdivided into equivalent unit dosage forms such as tablets, pills and capsules. Individual unit dosages may also contain film coatings, which disintegrate upon oral ingestion or upon contact with diluents. These formulations can be manufactured by conventional pharmacological techniques.

Conventional pharmacological techniques include, for example, one or a combination of the following methods: (1) dry blending, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, (5) wet granulation, or (6) Fusion. See, eg, Lachman et al., The Theory and Practice of Industrial Pharmacy (1986). Other methods include, for example, spray drying, pan coating, melt granulation, granulation, fluid bed spray drying or coating (e.g. Wurster coating), tangential coating, top spraying, tabletting, extrusion, etc. .

Pharmaceutical solid dosage forms described herein may comprise a compound described herein and one or more pharmaceutically acceptable additives, such as compatible carriers, binders, fillers, suspending agents, flavoring agents, sweeteners, disintegrating agents agent, dispersant, surfactant, lubricant, colorant, diluent, solubilizer, wetting agent, plasticizer, stabilizer, penetration enhancer, wetting agent, antifoaming agent, antioxidant, preservative, or One or more combinations thereof. In yet other aspects, compounds of the invention (e.g., compounds described above in the first to third aspects) are surrounded using standard coating procedures, such as those described in Remington's Pharmaceutical Sciences, 20th Edition (2000). ) formulations to provide a film coating. In one embodiment some or all of the particles of a compound of the invention (such as a compound described above in the first to third aspects) are coated. In another embodiment, some or all of the particles of a compound of the invention (such as a compound described in the first to third aspects above) are microencapsulated. In yet another embodiment, the particles of the compound of the invention (such as those described above in the first to third aspects) are neither microencapsulated nor coated.

Suitable carriers for use in the solid dosage forms described herein include, but are not limited to, gum arabic, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerin, magnesium silicate, sodium caseinate , soy lecithin, sodium chloride, tricalcium phosphate, dipotassium hydrogen phosphate, sodium stearoyl lactylate, carrageenan, monoglycerides, diglycerides, pregelatinized starch, hydroxypropyl methylcellulose, hydroxypropyl Methylcellulose acetate stearate, sucrose, microcrystalline cellulose, lactose, mannitol, etc.

Suitable fillers for use in the solid dosage forms described herein include, but are not limited to, lactose, calcium carbonate, calcium phosphate, calcium hydrogen phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrose , dextran, starch, pregelatinized starch, hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate stearate ( HPMCAS), sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, etc.

In order to release the compounds of the invention (such as those described in the first to third aspects above) from the solid dosage form matrix as efficiently as possible, disintegrants are often used in the formulation, especially when the dosage form is When the mixture is compressed. Disintegrants help break down the dosage form matrix by swelling or capillary action when moisture is absorbed into the dosage form. Suitable disintegrants for use in the solid dosage forms described herein include, but are not limited to, native starches such as corn starch or potato starch, pregelatinized starches such as National 1551 or or sodium starch glycolate such as or Cellulose such as wood products, methyl crystalline cellulose such as and Methylcellulose, croscarmellose, or crosslinked cellulose such as croscarmellose sodium Cross-linked carboxymethylcellulose or cross-linked croscarmellose, cross-linked starches such as sodium starch glycolate, cross-linked polymers such as crospovidone, cross-linked polyvinylpyrrolidone, alginic acid Salts such as alginic acid or salts of alginic acid such as sodium alginate, clays such as HV (magnesium aluminum silicate), gums such as agar, guar, locust bean, karaya, pectin or tragacanth, sodium starch glycolate, bentonite, natural sponges, surfactants, resins such as cation exchange Resins, citrus marc, sodium lauryl sulfate, combinations of sodium lauryl sulfate and starch, etc.

Binders impart cohesiveness to solid oral dosage form formulations: for powder-filled capsule formulations, they facilitate the formation of a tampon that can be filled into soft or hard shell capsules, while for tablet formulations they ensure that the tablet Retains integrity after pressing and helps ensure blend uniformity prior to pressing or filling steps. Materials suitable for use as binders in the solid dosage forms described herein include, but are not limited to, carboxymethylcellulose, methylcellulose (e.g. ), Hydroxypropylmethylcellulose (such as Hypromellose USP Pharmacoat-603, Hydroxypropylmethylcellulose Acetate Stearate (Aqoate HS-LF and HS), Hydroxypropylmethylcellulose, Hydroxypropylcellulose (E.g ), ethyl cellulose (eg ), and microcrystalline cellulose (such as ), microcrystalline dextrose, amylose, magnesium aluminum silicate, polysaccharide acid, bentonite, gelatin, polyvinylpyrrolidone/vinyl acetate copolymer, crospovidone, povidone, starch, pregelatinized starch , tragacanth, dextrin, sugars such as sucrose (eg ), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (eg ), lactose, natural or synthetic gums such as acacia, tragacanth, dava, isapol bark mucilage, starch, polyvinylpyrrolidone (eg CL, CL, XL-10 and K-12), larch arabinogalactan, Polyethylene glycol, wax, sodium alginate, etc.

Generally, binder levels of 20-70% are used in powder-filled gelatin capsule formulations. Binder usage levels in tablet formulations vary, whether direct compression, wet granulation, roller compaction, or use of other excipients such as fillers which themselves act as moderate binders. A formulator skilled in the art can determine the binder level for the formulation, but binder usage levels up to 70% are common in tablet formulations.

Suitable lubricants or glidants for use in the solid dosage forms described herein include, but are not limited to, stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, alkali metal and alkaline earth metal salts such as Aluminum salt, calcium salt, magnesium salt, zinc salt, stearic acid, sodium stearate, magnesium stearate, zinc stearate, wax, Boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, polyethylene glycol or methoxypolyethylene glycol such as Carbowax ^TM , PEG4000, PEG5000, PEG6000, propylene glycol, sodium oleate, glyceryl behenate, Glyceryl Palmitostearate, Glyceryl Benzoate, Magnesium Lauryl Sulfate or Sodium Lauryl Sulfate, etc.

Suitable diluents for use in the solid dosage forms described herein include, but are not limited to, sugars (including lactose, sucrose, and dextrose), polysaccharides (including dextrose and maltodextrin), polyalcohols (including mannitol, xylitol and sorbitol), cyclodextrin, etc.

The term "water-insoluble diluent" represents compounds typically used in pharmaceutical formulations, such as calcium phosphate, calcium sulfate, starch, modified starch, and microcrystalline cellulose, as well as microcellulose (e.g., having a density of about 0.45 g /cm3, such as Avicel, powdered cellulose) and talc.

Suitable humectants for use in the solid dosage forms described herein include, for example, oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, trioleate Ethanolamine, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, quaternary ammonium compounds (eg ), sodium oleate, sodium lauryl sulfate, magnesium stearate, sodium docusate, triacetin, vitamin E TPGS, etc.

Suitable surfactants for use in the solid dosage forms described herein include, for example, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbate Alcohol esters, polaxomers, bile salts, glyceryl monostearate, ethylene oxide and propylene oxide copolymers such as (BASF), and so on.

Suitable suspending agents for use in the solid dosage forms described herein include, but are not limited to, polyvinylpyrrolidones, such as polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25 or polyvinylpyrrolidone K30; polyethylene glycols, such as Polyethylene glycol may have a molecular weight of from about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400; vinylpyrrolidone/vinyl acetate copolymer (S630); sodium carboxymethylcellulose; hydroxypropylmethylcellulose; polysorbate-80; hydroxyethylcellulose; sodium alginate; gums such as tragacanth and acacia; guar gum; xanthan gums including tragacanth Raw gum; sugar; cellulosic materials such as sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose; polysorbate-80; Sodium alginate; polyethoxylated sorbitan monolaurate; polyethoxylated sorbitan monolaurate; povidone, etc.

Suitable antioxidants for use in the solid dosage forms described herein include, for example, butylated hydroxytoluene (BHT), sodium ascorbate, and tocopherol.

It should be appreciated that there is considerable overlap between the additives used in the solid dosage forms described herein. Accordingly, the additives listed above should be considered exemplary only, and not limiting, of the types of additives that may be included in the solid dosage forms described herein. The amount of such additives can be readily determined by those skilled in the art according to the particular properties desired.

In other embodiments, one or more layers of the pharmaceutical formulation are plasticized. Illustratively, plasticizers are generally high boiling solids or liquids. Suitable plasticizers can be added from about 0.01% to about 50% by weight (w/w) of the coating composition. Plasticizers include but are not limited to diethyl phthalate, citrates, polyethylene glycol, glycerin, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate , dibutyl sebacate, stearic acid, oleaginous agent, stearate and castor oil.

Compressed tablets are solid dosage forms prepared by compressing a bulk blend of the formulations described above. In various embodiments, compressed tablets designed to dissolve in the mouth will contain one or more flavoring agents. In other embodiments, the compressed tablet will comprise a film surrounding the final compressed tablet. In some embodiments, the film coating may provide for delayed release of the compound of the invention (eg, the compound described above in the first to third aspects) from the formulation. In other embodiments, film coating facilitates patient compliance (e.g. coating or sugar coating). Film coating includes Typically a tablet weight range of about 1% to about 3%. In other embodiments, compressed tablets comprise one or more excipients.

Capsules may be prepared, for example, by placing, inside a capsule, a bulk blend of the formulations of the compounds of the invention described above, such as those described in the first to third aspects above. In some embodiments, the formulations (non-aqueous suspensions and solutions) are placed in soft gelatin capsules. In other embodiments, the formulations are placed in standard gelatin capsules or non-gelatin capsules such as capsules comprising HPMC. In other embodiments, the formulation is placed in a sprinkle capsule, wherein the capsule can be swallowed whole or the capsule can be opened and the contents sprinkled on food before consumption. In some embodiments, the therapeutic dose is divided into multiple (eg, two, three, or four) capsules. In some embodiments, the entire dose of the formulation is delivered in one capsule.

In various embodiments, granules of a compound of the invention (such as those described above in the first to third aspects) and one or more excipients are dry blended and compressed into a block, such as a tablet, which has Hardness sufficient to provide in less than about 30 minutes, less than about 35 minutes, less than about 40 minutes, less than about 45 minutes, less than about 50 minutes, less than about 55 minutes, or less than about 60 minutes after oral administration A pharmaceutical composition that substantially disintegrates in the body to release the formulation into the gastrointestinal fluids.

In another aspect, dosage forms can include microencapsulated formulations. In some embodiments, one or more other compatible materials are present in the microencapsulated material. Exemplary materials include, but are not limited to, pH adjusters, erosion promoters, antifoaming agents, antioxidants, flavoring agents, and carrier materials such as binders, suspending agents, disintegrants, fillers, surfactants, solubilizers, Stabilizers, lubricants, wetting agents and diluents.

Materials useful for microencapsulation as described herein include materials compatible with the compounds of the invention (such as those described in the first to third aspects above) that are sufficient to sequester the compounds of the invention (such as those described in the first to third aspects above). compounds described in the third aspect) and other incompatible excipients. Materials compatible with the compounds of the invention (such as those described in the first to third aspects above) are materials that delay the release of the compounds of the invention (such as the compounds described in the first to third aspects above) in vivo of those.

Exemplary microencapsulating materials useful for delaying the release of formulations comprising the compounds described herein include, but are not limited to, hydroxypropyl cellulose ether (HPC) such as Or Nisso HPC, low substituted hydroxypropyl cellulose ether (L-HPC), hydroxypropyl methyl cellulose ether (HPMC) such as Seppifilm-LC, Metolose SR, Opadry YS, PrimaFlo, Benecel MP824 and Benecel MP843, methylcellulose polymers such as Hydroxypropyl methylcellulose acetate stearate Aqoat (HF-LS, HF-LG, HF-MS) and Ethylcellulose (EC) and its mixtures such as E461, Polyvinyl alcohol (PVA) such as Opadry AMB, hydroxyethyl cellulose such as Carboxymethylcellulose (CMC) and salts of carboxymethylcellulose such as Copolymers of polyvinyl alcohol and polyethylene glycol such as Monoglycerides (Myverol), triglycerides (KLX), polyethylene glycols, modified food starches, acrylic polymers and mixtures of acrylic polymers with cellulose ethers such as and Cellulose acetate phthalates, sepiflms such as mixtures of HPMC and stearic acid, cyclodextrins, and mixtures of these materials.

In yet other embodiments, plasticizers such as polyethylene glycols such as PEG300, PEG400, PEG600, PEG1450, PEG3350, and PEG800, stearic acid, propylene glycol, oleic acid, and triacetin are incorporated into the microcapsules in chemical materials. In other embodiments, microencapsulation materials useful for delaying the release of pharmaceutical compositions are from the USP or National Formulary (NF). In still other embodiments, the microencapsulating material is Klucel. In still other embodiments, the microencapsulation material is methocel.

The microencapsulated compounds of the present invention (eg, the compounds described in the first to third aspects above) can be formulated by methods known to those of ordinary skill in the art. Such known methods include, for example, spray drying, rotating disk-solvent, hot melt, spray cooling, fluidized bed, electrostatic deposition, centrifugal extrusion, rotary suspension separation, liquid-gas or solid-gas interfacial polymerization, Pressure extruded or sprayed solvent extraction baths. Besides these, several chemical techniques such as complex coacervation, solvent evaporation, interpolymer incompatibility, interfacial polymerization in liquid medium, in situ polymerization, drying in liquid, and desolvation in liquid medium can be used. Furthermore, other methods such as roller compaction, extrusion/spheronization, coacervation or nanoparticle coating may also be used.

In one embodiment, particles of a compound of the invention, such as those described in the first to third aspects above, are microencapsulated prior to being formulated into one of the above forms. In yet another embodiment, some or most of the granules are coated prior to being further formulated using standard coating procedures, such as those described in Remington's Pharmaceutical Sciences, 20th Edition (2000).

In other embodiments, a solid dosage formulation of a compound of the invention (eg, a compound described above in the first to third aspects) is plasticized (coated) with one or more layers. Illustratively, plasticizers are generally high boiling solids or liquids. Suitable plasticizers can be added from about 0.01% to about 50% by weight (w/w) of the coating composition. Plasticizers include but are not limited to diethyl phthalate, citrate, polyethylene glycol, glycerin, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate , dibutyl sebacate, stearic acid, oleaginous agent, stearate and castor oil.

In other embodiments, powders of formulations comprising compounds of the invention, such as those described above in the first to third aspects, may be formulated to contain one or more pharmaceutical excipients and flavoring agents. Such powders can be prepared, for example, by mixing the formulation and optional pharmaceutical excipients to form a bulk blend composition. Additional embodiments also include suspending and/or wetting agents. This bulk blend is uniformly subdivided into unit-dose packaging or multi-dose packaging units.

In still other embodiments, effervescent powders are also prepared in accordance with the present disclosure. Effervescent salts have been used to disperse drugs in water for oral administration. Effervescent salts are granules or coarse powders containing medicinal agents in a dry mixture, usually consisting of sodium bicarbonate, citric acid, and/or tartaric acid. When a salt of a composition described herein is added to water, the acid and base react to release carbon dioxide gas, resulting in "effervescence." Examples of effervescent salts include ingredients such as sodium bicarbonate or a mixture of sodium bicarbonate and sodium carbonate, citric acid and/or tartaric acid. Any acid-base combination that results in the release of carbon dioxide can be used in place of sodium bicarbonate and the combination of citric and tartaric acids, as long as the ingredients are suitable for pharmaceutical use and the resulting pH is about 6.0 or higher.

In other embodiments, the formulations described herein comprising a compound of Formula (A) are solid dispersions. Methods of producing such solid dispersions are known in the art and include, but are not limited to, for example, U.S. Patent Nos. 4,343,789, 5,340,591, 5,456,923, 5,700,485, 5,723,269, and U.S. Published Application 2004/0013734, each of which is expressly incorporated by reference. In yet other embodiments, the formulations described herein are solid solutions. Solid solutions incorporate the substance simultaneously with the active agent and other excipients such that heating the mixture results in dissolution of the drug and then cooling the resulting composition to provide a solid blend that can be further formulated or added directly into capsules or compressed into tablets. Methods of producing such solid solutions are known in the art and include, but are not limited to, for example, US Patent Nos. 4,151,273, 5,281,420, and 6,083,518, each of which is expressly incorporated by reference.

A pharmaceutical solid oral dosage form comprising a formulation described herein comprising a compound of the invention (eg, a compound described in the first to third aspects above) may be further formulated to provide controlled release of the compound of formula (A) . Controlled release refers to the release of the compound of the invention (such as those described above in the first to third aspects) from the dosage form into which it is incorporated over an extended period of time according to desired characteristics. Controlled-release characteristics include, for example, sustained-release, extended-release, pulsatile-release and delayed-release characteristics. Relative to immediate release compositions, controlled release compositions allow the delivery of an agent to a subject according to predetermined characteristics over an extended period of time. Such release rates can provide therapeutically effective levels of the agent over an extended period of time, thereby minimizing side effects while providing a longer period of pharmacological response than conventional immediate release dosage forms. Such longer periods of response provide many inherent benefits unattainable with corresponding short-acting immediate release formulations.

In some embodiments, the solid dosage forms described herein can be formulated as enteric-coated extended-release oral dosage forms, i.e., oral dosage forms of pharmaceutical compositions as described herein that utilize an enteric coating to affect the freed. Enteric-coated dosage forms may be compressed or molded or extruded tablets/moulds (coated or uncoated), containing granules, powders, pellets, beads or granules of the active ingredient and/or other composition ingredients, which Self-coated or uncoated. Enteric-coated oral dosage forms can also be capsules (coated or uncoated), pellets, beads or granules comprising a solid carrier or composition, themselves coated or uncoated.

The term "extended release" as used herein refers to delivery such that release can be accomplished at some generally predictable location in the intestinal tract that is more distal than it would be if release were not altered. In some embodiments, the method of delaying release is coating. Any coating should be applied in sufficient thickness such that the entire coating does not dissolve in gastrointestinal fluids at a pH below about 5, but does dissolve at a pH of about 5 and above. It is contemplated that any anionic polymer exhibiting a pH-dependent solubility profile may be used as an enteric coating in the methods and compositions described herein to achieve delivery to the lower gastrointestinal tract. In some embodiments, the polymers described herein are anionic carboxylic acid polymers. In other embodiments, polymers and compatible mixtures thereof, as well as some of their properties, include, but are not limited to:

Lac shellac, also called purified shellac, is a refined product obtained from the resinous secretions of insects. This coating dissolves in media with a pH > 7;

Acrylic polymer. The properties of acrylic polymers, primarily their solubility in biological fluids, can vary based on the degree and type of substitution. Examples of suitable acrylic polymers include methacrylic acid copolymers and ammonium methacrylate copolymers. Eudragit series E, L, S, RL, RS and NE (Rohm Pharma) are available as dissolved in organic solvents, aqueous dispersions or dry powders. The Eudragit series RL, NE, and RS are insoluble in the gastrointestinal tract, but permeable, and are primarily used to target the colon. Eudragit Series E dissolves in the stomach. Eudragit series L, L-30D and S are insoluble in the stomach but dissolve in the intestine;

Cellulose derivatives. Examples of suitable cellulose derivatives are: ethyl cellulose; reaction mixtures of partial acetates of cellulose and phthalic anhydride. Properties may vary based on the degree and type of substitution. Cellulose acetate phthalate (CAP) dissolves at pH >6. Aquateric (FMC) is an aqueous based system and is a spray-dried CAP pseudolatex with particles <1 Mm. Other ingredients in Aquateric may include Pluronics, Tweens, and Acetylated Monoglycerides. Other suitable cellulose derivatives include: cellulose acetate trimellitate (Eastman); methylcellulose (Pharmacoat, Methocel); hydroxypropylmethylcellulose phthalate (HPMCP); Propylmethylcellulose succinate (HPMCS); and hydroxypropylmethylcellulose acetate succinate (eg AQOAT (Shin Etsu)). Properties may vary based on the degree and type of substitution. For example, grades of HPMCP such as HP-50, HP-55, HP-55S, HP-55F are suitable. Properties may vary based on the degree and type of substitution. For example, suitable grades of hydroxypropylmethylcellulose acetate succinate include, but are not limited to, AS-LG (LF), which dissolves at pH 5; AS-MG (MF), which dissolves at pH 5.5; and AS- HG(HF), which dissolves at higher pH. These polymers are supplied as granules or fine powders for use in aqueous dispersions;

Polyvinyl acetate phthalate (PVAP). PVAP dissolves at pH > 5, and it is much less permeable to moisture and gastric juices.

In some embodiments, the coating can, and often does, contain plasticizers and other possible coating excipients such as colorants, talc, and/or magnesium stearate, as are well known in the art. Suitable plasticizers include triethyl citrate (Citroflex2), glycerol triacetate (triacetin), acetyl triethyl citrate (Citroflec A2), Carbowax 400 (polyethylene glycol 400), o-phthalic acid Diethyl dicarboxylate, tributyl citrate, acetylated monoglycerides, glycerin, fatty acid esters, propylene glycol, and dibutyl phthalate. In particular, anionic carboxylic acrylic polymers will generally contain 10-25% by weight of plasticizers, especially dibutyl phthalate, polyethylene glycol, triethyl citrate and triacetin. The coating is applied using conventional coating techniques such as spray or pan coating. The thickness of the coating must be sufficient to ensure that the oral dosage form remains intact until it reaches the desired topical delivery site in the intestinal tract.

In addition to plasticizers, colorants, anti-tacking agents, surfactants, anti-foaming agents, lubricants (such as carnauba wax or PEG) can also be added to the coating to dissolve or disperse the coating material and improve the coating Properties and coated products.

In other embodiments, the formulations described herein comprising a compound of Formula (A) are delivered using a pulsatile dosage form. A pulsatile dosage form is capable of providing one or more immediate release pulses at predetermined time points or at specific sites after a controllable delay time. A pulsatile dosage form comprising a formulation described herein comprising a compound of the invention (eg, a compound described in the first to third aspects above) may be administered using various pulsatile formulations known in the art. For example, such formulations include, but are not limited to, those described in US Patent Nos. 5,011,692, 5,017,381, 5,229,135, and 5,840,329, each of which is expressly incorporated by reference. Other pulsed release dosage forms suitable for use with the present formulations include, but are not limited to, for example, US Patent Nos. 4,871,549, 5,260,068, 5,260,069, 5,508,040, 5,567,441 and 5,837,284, all of which are expressly incorporated by reference. In one embodiment, the controlled release dosage form is a pulsed release solid oral dosage form comprising at least two groups of particles (ie, multiparticulates), each comprising a formulation described herein. The first set of particles provides a substantially immediate dose of a compound of the invention, such as a compound described in the first to third aspects above, when ingested by a mammal. The particles of the first group may be uncoated, or contain coatings and/or sealants. The second group of granules includes coated granules comprising about 2% to about 75%, about 2.5% to about 70%, or about 40% to about 70% by weight of the compound of the present invention in the formulation ( Such as the compounds described in the first to third aspects above), mixed with one or more binders. The coating comprises a pharmaceutically acceptable ingredient in an amount sufficient to provide a delay of about 2 hours to about 7 hours after ingestion before release of the second dose. Suitable coatings include one or more differentially degradable coatings such as, by way of example only, pH sensitive coatings (enteric coatings), e.g. alone or blended with cellulose derivatives such as ethyl cellulose acrylic resin (such as ), or a non-enteric coating of varying thickness to provide differential release of a formulation comprising a compound of the invention (eg, a compound described in the first to third aspects above).

Many other types of controlled release systems are known to those of ordinary skill in the art and are suitable for use with the formulations described herein. Examples of such delivery systems include, for example, polymer-based systems such as polylactic and polyglycolic acids, polyanhydrides and polycaprolactones; porous matrices; non-polymer-based systems that are lipids, including sterols such as cholesterol, cholesterol Esters and fatty acids, or neutral fats such as mono-, di-, and triglycerides; hydrogel delivery systems; silicone rubber systems; peptide-based systems; wax-coated, bioerodible dosage forms, compressed tablets using conventional binders ,and many more. See, eg, Liberman et al., Pharmaceutical Dosage Forms, 2nd Ed., Vol. 1, pp. 209-214 (1990); Singh et al., Encyclopedia of Pharmaceutical Technology, 2nd Ed., pp. 751-753 (2002); U.S. Pat. Nos. 4,327,725, 4,624,848 , 4,968,509, 5,461,140, 5,456,923, 5,516,527, 5,622,721, 5,686,105, 5,700,410, 5,977,175, 6,465,014, and 6,932,983, each of which is expressly incorporated by reference.

In some embodiments, there is provided a pharmaceutical formulation comprising particles of a compound of the invention (eg, a compound described in the first to third aspects above) and at least one dispersing or suspending agent for oral administration to a subject. The formulations may be powders and/or granules for suspension and when mixed with water give a substantially homogeneous suspension.

Liquid formulation dosage forms for oral administration may be aqueous suspensions selected from the group including, but not limited to, pharmaceutically acceptable aqueous oral dispersions, emulsions, solutions, elixirs, gels and syrups. See, eg, Singh et al., Encyclopedia of Pharmaceutical Technology, 2nd Edition, pp. 754-757 (2002). In addition to the granules of the compound of formula (A), the liquid dosage form may contain additives such as: (a) disintegrants; (b) dispersants; (c) wetting agents; (d) at least one preservative, ( e) a thickener, (f) at least one sweetener, and (g) at least one flavoring agent. In some embodiments, the aqueous dispersant may further comprise a crystallization inhibitor.

The aqueous suspensions and dispersions described herein can be maintained in a homogeneous state, as defined in the USP Pharmacist's Pharmacopoeia (2005 Edition, Chapter 905), for at least 4 hours. Uniformity should be determined by a sampling method consistent with determining the uniformity of the entire composition. In one embodiment, an aqueous suspension can be resuspended into a homogeneous suspension by physical shaking lasting less than 1 minute. In another embodiment, an aqueous suspension can be resuspended into a homogeneous suspension by physical shaking lasting less than 45 seconds. In yet another embodiment, the aqueous suspension can be resuspended into a homogeneous suspension by physical shaking lasting less than 30 seconds. In yet another embodiment, shaking is not required to maintain a homogeneous aqueous dispersion.

Examples of disintegrants used in aqueous suspensions and dispersions include, but are not limited to, starches such as native starches, such as corn starch or potato starch, pregelatinized starches such as National 1551 or or sodium starch glycolate such as or Cellulose such as wood products, methyl crystalline cellulose such as and Methylcellulose, croscarmellose, or crosslinked cellulose such as croscarmellose sodium Cross-linked carboxymethylcellulose or cross-linked croscarmellose; cross-linked starches such as sodium starch glycolate; cross-linked polymers such as crospovidone; cross-linked polyvinylpyrrolidone; alginic acid Salts such as alginic acid or salts of alginic acid such as sodium alginate; clays such as HV (magnesium aluminum silicate); gums such as agar, guar, locust bean, karaya, pectin or tragacanth; sodium starch glycolate; bentonite; natural sponges; surfactants; resins such as cation exchange resins; citrus pomace; sodium lauryl sulfate; combinations of sodium lauryl sulfate and starch;

In some embodiments, suitable dispersing agents for the aqueous suspensions and dispersions described herein are known in the art and include, for example, hydrophilic polymers, electrolytes, or 80, PEG, polyvinylpyrrolidone (PVP; commercially known as ) and carbohydrate-based dispersants such as hydroxypropylcellulose and hydroxypropylcellulose ethers (such as HPC, HPC-SL and HPC-L), hydroxypropylmethylcellulose and hydroxypropylmethylcellulose Ethers (such as HPMC K100, HPMC K4M, HPMC K15M, and HPMC K100M), sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropyl Methylcellulose acetate stearate, amorphous cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), polyvinylpyrrolidone/vinyl acetate copolymer ( Such as S-630), 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde (also known as tyloxapol), poloxamer ( E.g and which are block copolymers of ethylene oxide and propylene oxide); and poloxamines (such as also known as It is a tetrafunctional block copolymer derived from the sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Corporation, Parsippany, NJ)). In other embodiments, the dispersant is selected from a group that does not include one of the following agents: a hydrophilic polymer; an electrolyte; 60 or 80; PEG; polyvinylpyrrolidone (PVP); hydroxypropylcellulose and hydroxypropylcellulose ethers (such as HPC, HPC-SL, and HPC-L); hydroxypropylmethylcellulose and hypromellose Base cellulose ethers (such as HPMC K100, HPMCK4M, HPMC K15M, HPMC K100M and USP2910 (Shin-Etsu)); Sodium carboxymethylcellulose; Methylcellulose; Hydroxyethylcellulose; Hydroxypropylmethylcellulose phthalate; Hydroxypropylmethylcellulose acetate hard fatty acid ester; amorphous cellulose; magnesium aluminum silicate; triethanolamine; polyvinyl alcohol (PVA); 4-(1,1,3,3-tetramethylbutyl)-phenol with ethylene oxide and Polymers of formaldehyde; poloxamers (e.g. and which are block copolymers of ethylene oxide and propylene oxide); or poloxamines (such as also known as ).

Wetting agents suitable for the aqueous suspensions and dispersions described herein are known in the art and include, but are not limited to, cetyl alcohol, glyceryl monostearate, polyoxyethylene sorbitan fatty acid esters (e.g., commercially available E.g and (ICI Specialty Chemicals)) and polyethylene glycol (e.g. and as well as (Union Carbide)), Oleic Acid, Glyceryl Monostearate, Sorbitan Monooleate, Sorbitan Monolaurate, Triethanolamine Oleate, Polyoxyethylene Sorbitan Monooleate, Polyoxyethylene Sorbitan Monolaurate, Sodium Oleate, Sodium Lauryl Sulfate, Sodium Docusate, Triacetin, Vitamin E TPGS, Sodium Taurocholate, Dimethicone, Phosphatidylcholine, etc.

Suitable preservatives for the aqueous suspensions or dispersions described herein include, for example, potassium sorbate, parabens (such as methylparaben and propylparaben), benzoic acid and its salts, paraben Other esters such as butylparaben, alcohols such as ethanol or benzyl alcohol, phenolic compounds such as phenol, or quaternary ammonium compounds such as benzalkonium chloride. As used herein, preservatives are incorporated into dosage forms at concentrations sufficient to inhibit the growth of microorganisms.

Suitable thickeners for the aqueous suspensions or dispersions described herein include, but are not limited to, methylcellulose, xanthan gum, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, S-630, carbomer, polyvinyl alcohol, alginate, acacia, chitosan, and combinations thereof. The concentration of thickener will depend on the agent chosen and the viscosity desired.

Examples of sweeteners suitable for the aqueous suspensions or dispersions described herein include, for example, acacia syrup, acesulfame K, alitame, fennel, apple, aspartame, banana, Bavarian cream, berries, black currant , butterscotch, calcium citrate, camphor, caramel, cherries, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, marshmallow, cocoa, cola, cold cherries, cold citrus, Cyclamate, cylamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinic acid, licorice (licorice) syrup, grape, grapefruit, honey, isomaltulose Alcohol, Lemon, Lime, Lemon Cream, Monoammonium Glycyrrhizinate Maltol, Mannitol, Maple, Marshmallow, Menthol, Peppermint Cream, Mixed Berries, Neohesperidin DC, Neotame, Orange, Pear, Peach, Peppermint, Peppermint Cream, Powder, Raspberry, Root Root, Rum, Saccharin, Safrole, Sorbitol, Spearmint, Spearmint Cream, Strawberry, Strawberry Cream, Stevia, Sucralose, Sucrose, Sodium Saccharin, Saccharin, Aspartame , acesulfame potassium, mannitol, talin, sucralose, sorbitol, swiss cream, tagatose, orange, thaumatin, mincemeat, vanilla, walnut, watermelon, wild cherry, wintergreen, xylitol , or any combination of these flavoring ingredients, such as anise-menthol, cherry-fennel, cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus, orange -cream, vanilla-mint, and mixtures thereof. In one embodiment, the aqueous liquid dispersion may contain a sweetening or flavoring agent at a concentration ranging from about 0.001% to about 1.0% by volume of the aqueous dispersion. In another embodiment, the aqueous liquid dispersion may contain a sweetening or flavoring agent at a concentration ranging from about 0.005% to about 0.5% by volume of the aqueous dispersion. In yet another embodiment, the aqueous liquid dispersion may contain a sweetening or flavoring agent at a concentration ranging from about 0.01% to about 1.0% by volume of the aqueous dispersion.

In addition to the above-listed additives, liquid formulations may also contain inert diluents such as water or other solvents, solubilizers and emulsifiers commonly used in the art. Exemplary emulsifiers are ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, sodium lauryl sulfate , docusate sodium, cholesterol, cholesteryl esters, taurocholic acid, phosphatidylcholine, oils such as cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol , fatty acid esters of sorbitan, or mixtures of these substances, etc.

In some embodiments, the pharmaceutical formulations described herein may be self-emulsifying drug delivery systems (SEDDS). An emulsion is a dispersion of one immiscible phase in another, usually in the form of small droplets. Generally, emulsions are formed by vigorous mechanical dispersion. In contrast to emulsions or microemulsions, SEDDS spontaneously forms emulsions when added to excess water without any external mechanical dispersion or shaking. One advantage of SEDDS is that only gentle mixing is required to spread the small droplets throughout the solution. Furthermore, water or an aqueous phase can be added shortly before application, which ensures the stability of unstable or hydrophobic active ingredients. Therefore, SEDDS provides an efficient delivery system for oral and parenteral delivery of hydrophobic active ingredients. SEDDS can provide improved bioavailability of hydrophobic active ingredients. Methods of producing self-emulsifying dosage forms are known in the art and include, but are not limited to, for example, US Patent Nos. 5,858,401, 6,667,048, and 6,960,563, each of which is expressly incorporated by reference.

It will be appreciated that there is overlap between the additives listed above for use in the aqueous dispersions or suspensions described herein, as a given additive is often classified differently by different practitioners in the art, or serves several different functions use any of them. Accordingly, the above-listed additives should be considered exemplary only, and not limiting, of the types of additives that may be included in the formulations described herein. The amount of such additives can be readily determined by those skilled in the art according to the particular properties desired.

Intranasal preparations

Intranasal formulations are known in the art and are described, for example, in US Patent Nos. 4,476,116, 5,116,817 and 6,391,452, each of which is expressly incorporated by reference. Formulations comprising compounds of the invention (such as those described in the first to third aspects above) prepared according to these and other techniques well known in the art, using benzyl alcohol or other suitable preservatives, fluorocarbons and/or Other solubilizing or dispersing agents known in the art are prepared as solutions in saline. See, eg, Ansel, H.C. et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, Sixth Edition (1995). Preferably, these compositions and formulations are prepared using suitable non-toxic pharmaceutically acceptable ingredients. These ingredients are known to those skilled in the preparation of nasal dosage forms and some of them can be found in REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY, 21st Edition, 2005, a standard reference in this field. The choice of a suitable carrier is highly dependent on the exact nature of the desired nasal dosage form, eg solution, suspension, ointment or gel. Nasal dosage forms generally contain large amounts of water in addition to the active ingredient. Minor amounts of other ingredients such as pH adjusters, emulsifying or dispersing agents, preservatives, surfactants, gelling or buffering agents and other stabilizing and solubilizing agents may also be present. Nasal dosage forms should be isotonic with nasal secretions.

For administration by inhalation, the compounds of the invention (such as those described above in the first to third aspects) may be in aerosol, mist or powder form. The pharmaceutical compositions described herein are conveniently delivered in the form of an aerosol spray from a pressurized pack or nebulizer using a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoromethane, Ethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a measured amount. Capsules and kits of gelatin, eg, by way of example only, for use in an inhaler or insufflator may be formulated containing a powder mix of the compound described herein and a suitable powder base such as lactose or starch.

Oral preparations

Oral formulations comprising a compound of the invention, such as those described above in the first to third aspects, may be administered using a variety of formulations known in the art. For example, such formulations include, but are not limited to, US Patent Nos. 4,229,447, 4,596,795, 4,755,386, and 5,739,136, each of which is expressly incorporated by reference. Additionally, the oral dosage forms described herein may further comprise a bioerodible (hydrolyzable) polymeric carrier that also serves to adhere the dosage form to the oral mucosa. The oral dosage form is prepared so as to gradually erode over a predetermined period of time, wherein delivery of a compound of the invention (eg, a compound described above in the first to third aspects) is provided substantially throughout. As will be appreciated by those skilled in the art, oral drug delivery avoids the disadvantages encountered with oral drug administration, such as slow absorption, degradation of the active agent by fluids present in the gastrointestinal tract, and/or first-pass inactivation in the liver. In the case of bioerodible (hydrolyzed) polymeric carriers, it will be appreciated that virtually any such carrier can be used as long as the desired drug release profile is not compromised and the carrier is compatible with the compounds of the invention (e.g. first to first above). The compounds described in the third aspect) are compatible with any other ingredients that may be present in the oral dosage unit. Generally, the polymeric carrier comprises a hydrophilic (water-soluble and water-swellable) polymer that adheres to the wetted surface of the oral mucosa. Examples of polymeric carriers useful herein include acrylic acid polymers and copolymers, such as those known as "carbomers" ( available from BF Goodrich, is one such polymer). Other ingredients may also be incorporated into the oral dosage forms described herein, including, but not limited to, disintegrants, diluents, binders, lubricants, flavoring agents, coloring agents, preservatives, and the like. For buccal or sublingual administration, the compositions may take the form of tablets, lozenges or gels formulated in conventional manner.

transdermal preparation

The transdermal formulations described herein can be administered using a variety of devices that have been described in the art.例如，此类装置包括但不限于美国专利号3,598,122、3,598,123、3,710,795、3,731,683、3,742,951、3,814,097、3,921,636、3,972,995、3,993,072、3,993,073、3,996,934、4,031,894、4,060,084、4,069,307、4,077,407、4,201,211、4,230,105、4,292,299、4,292,303、 5,336,168, 5,665,378, 5,837,280, 5,869,090, 6,923,983, 6,929,801 and 6,946,144, each of which is expressly incorporated by reference in its entirety.

The transdermal dosage forms described herein may incorporate certain pharmaceutically acceptable excipients conventional in the art. In one embodiment, the transdermal formulations described herein comprise at least three components: (1) a formulation of a compound of the invention (eg, the compounds described above in the first to third aspects); (2) a penetration enhancer; and (3) an aqueous adjuvant. In addition, transdermal formulations may contain additional ingredients such as, but not limited to, gelling agents, cream and ointment bases, and the like. In some embodiments, the transdermal formulation may further comprise a woven or nonwoven backing material to enhance absorption and prevent removal of the transdermal formulation from the skin. In other embodiments, the transdermal formulations described herein can be maintained in a saturated or supersaturated state to facilitate diffusion into the skin.

Formulations suitable for transdermal administration of the compounds described herein may employ transdermal delivery devices and transdermal delivery patches, and may be lipophilic emulsions or buffered aqueous solutions, dissolved and/or dispersed in polymers or adhesives . Such patches can be configured for continuous, pulsatile, or on-demand delivery of pharmaceutical agents. Still further, transdermal delivery of the compounds described herein can be accomplished by means such as iontophoretic patches. In addition, transdermal patches may provide controlled delivery of compounds of the invention, such as those described in the first to third aspects above. The rate of absorption can be slowed by the use of rate-controlling membranes, or by trapping the compound within a polymer matrix or gel. Instead, absorption enhancers may be used to increase absorption. Absorption enhancers or carriers may include absorbable pharmaceutically acceptable solvents to assist passage through the skin. For example, a transdermal device is in the form of a bandage comprising a backing portion; a reservoir comprising a compound, optionally comprising a carrier; an optional rate-controlling barrier to deliver the drug to the host at a controlled, predetermined rate over an extended period of time. and a means for securing the device to the skin.

Injectable Formulations

Formulations comprising a compound of the invention (such as those described in the first to third aspects above) suitable for intramuscular, subcutaneous or intravenous injection may include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions , suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, cremophor, etc.), suitable mixtures thereof, vegetable oils (eg olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coatings such as lecithin, by maintaining the desired particle size in the case of dispersions, and by the use of surfactants. Formulations suitable for subcutaneous injection may also contain additives such as preserving, wetting, emulsifying, and dispersing agents. Prevention of the growth of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable drug forms can be brought about by the use of absorption delaying agents, such as aluminum monostearate and gelatin.

For intravenous injection, the compounds described herein can be formulated in aqueous solutions, preferably, physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are well known in the art. For other parenteral injections, appropriate formulations may include aqueous or non-aqueous solutions, preferably containing physiologically compatible buffers or excipients. Such excipients are well known in the art.

Parenteral injection can include bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, eg, in ampoules or in multi-dose containers, with an added preservative. The pharmaceutical compositions described herein may be in a form suitable for parenteral injection, such as sterile suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and/or dispersing agents . Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, eg sterile pyrogen-free water, before use.

other preparations

In certain embodiments, delivery systems for pharmaceutical compounds, such as liposomes and emulsions, may be used. In certain embodiments, the compositions provided herein may also comprise a mucoadhesive polymer selected from, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methyl methacrylate), polypropylene Amide, polycarbophil, acrylic acid/butyl acrylate copolymer, sodium alginate and dextran.

In some embodiments, the compounds described herein may be administered topically and may be formulated into a variety of topically administrable compositions such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, In cream or ointment. Such pharmaceutical compounds may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.

The compounds described herein may also be formulated into rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas containing conventional suppository bases such as cocoa butter or other glycerin Esters, and synthetic polymers such as polyvinylpyrrolidone, PEG, etc. In suppository form of the composition, a low melting wax, such as, but not limited to, a mixture of fatty acid glycerides, optionally in association with cocoa butter is first melted.

Examples of administration methods and treatment regimens

The compounds described herein are, in some embodiments, useful in the manufacture of a medicament for inhibiting Btk or a homolog thereof or for treating a disease or condition which would benefit at least in part from inhibition of Btk or a homolog thereof. Additionally, methods of treating any of the diseases or conditions described herein in an individual in need of such treatment comprise administering to said individual a pharmaceutical composition comprising at least one compound of the invention (e.g., The compound described in the first to third aspects) or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable N-oxide, a pharmaceutically active metabolite, a pharmaceutically acceptable prodrug, or a pharmaceutically acceptable solvate.

In other embodiments, compositions comprising compounds described herein are administered for prophylactic and/or therapeutic treatment. In therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician.

In prophylactic applications, a composition comprising a compound described herein is administered to a patient susceptible to or at risk of developing a particular disease, disorder or condition. Such an amount is defined as a "prophylactically effective amount or dose". In this application, the precise amount will also depend on the patient's state of health, weight, and the like. When used in a patient, amounts effective for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.

In some embodiments, the kinase inhibitor is administered to the patient on a regular basis, eg, three times a day, twice a day, once a day, every other day, or every 3 days. In other embodiments, the patient is administered the kinase inhibitor intermittently, for example twice a day, then once a day, then three times a day; or the first two days of each week; or the first, second, and third days of the week . In some embodiments, intermittent dosing is as effective as regular dosing. In further or alternative embodiments, the kinase inhibitor is administered only when the patient exhibits a specific symptom, such as the onset of pain, or the onset of fever, or the onset of inflammation, or the onset of skin disease.

In cases where the patient's condition does not improve, at the physician's discretion, the administration of the compound may be administered chronically, that is, for an extended period of time, including the entire duration of the patient's life, with the aim of ameliorating or controlling or limiting the patient's disease or symptoms of the condition.

In cases where the patient's condition does improve, at the discretion of the physician, administration of the compound may be continued; alternatively, the dose of drug administered may be temporarily reduced or suspended for a certain length of time (ie, a "drug holiday"). The length of the drug holiday can vary between 2 days and 1 year, including, by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days or 365 days. Dose reductions during drug holidays can be from about 10% to about 100%, including, by way of example only, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40% , about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%.

Once the patient's condition improves, a maintenance dose is administered, if necessary. Subsequently, the dosage or the frequency of administration, or both, may be reduced as symptoms change to a level at which the improvement in the disease, disorder or condition is maintained. However, patients may require intermittent treatment on a long-term basis upon any recurrence of symptoms.

The amount of a given agent corresponding to this amount will vary depending on factors such as the particular compound, the disease or condition and its severity, the characteristics (e.g. body weight) of the individual or host requiring treatment, and will be tailored to the particular circumstances of the case. As determined, such circumstances include, for example, the particular agent administered, the route of administration, the condition being treated, and the individual or host being treated. In general, however, dosages for adult human treatment will typically range from about 0.02 to about 5000 mg per day, or from about 1 to about 1500 mg per day. The desired dose may conveniently be presented in a single dose or as divided doses administered simultaneously (or within a short period of time) or at appropriate intervals, for example two, three, four or more sub-doses per day. dose.

The pharmaceutical compositions described herein may be in unit dosage form suitable for precise dosage for single administration. In unit dosage form, the preparation is divided into unit doses containing appropriate quantities of one or more compounds. The unit dosage can be in the form of a package containing discrete quantities of preparation. Non-limiting examples are packaged tablets or capsules, and powders in vials or ampoules. Aqueous suspension compositions may be packaged in non-resealable single-dose containers. Alternatively, resealable multi-dose containers may be employed, in which case a preservative will typically be included in the composition. By way of example only, formulations for parenteral injection may be presented in unit dosage form including, but not limited to, ampoules, or in multi-dose containers, with an added preservative.

The foregoing ranges are suggestive only, as the number of variables for individual treatment regimens is large and considerable deviations from these recommended values are not uncommon. Such dosages may vary, depending on many variables, not limited to the activity of the compound employed, the disease or condition being treated, the mode of administration, the needs of the individual individual, the severity of the disease or condition being treated, and the judgment of the practitioner.

The toxicity and therapeutic effects of such treatment regimens can be determined in cell culture or experimental animals by standard pharmaceutical procedures, including but not limited to LD50 values (50% lethal dose of the population) and ED50 values (50% therapeutically effective dose of the population) determination. The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio between LD50 and ED50 values. Compounds which exhibit high therapeutic indices are preferred. The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with minimal toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.

Increased Selective Dosing Strategies

Kinase inhibitors that are selective for one or more ACKs, including Btk, Btk homologs, and Btk kinase cysteine homologs, are described herein. In some embodiments, the inhibitors described herein also reversibly bind to other kinases (in some embodiments, some of which are also ACKs). As a means of enhancing the selectivity profile, such inhibitors are formulated (formulation including chemical modification of the inhibitor, use of excipients in pharmaceutical compositions, and combinations thereof) such that their pharmacokinetic profile relative to non-ACK It is more beneficial to enhance the selectivity of inhibitors to ACK. By way of example only, ACK is formulated to have a short plasma half-life. In other embodiments, the ACK is formulated to have an extended plasma half-life.

In one embodiment is a kinase inhibitor that selectively and irreversibly binds to a protein tyrosine kinase selected from the group consisting of Btk, Btk homologs and Btk kinase cysteine homologs, wherein the kinase inhibitor is reversible and non-selective binds selectively to a number of protein tyrosine kinases, and further wherein the kinase inhibitor has a plasma half-life of less than about 4 hours. In such an embodiment, the kinase inhibitor selectively and irreversibly binds to at least one of Btk, Jak3, Blk, Bmx, Tec, and Itk. In a further embodiment, the kinase inhibitor binds selectively and irreversibly to Btk. In a further embodiment, the kinase inhibitor binds selectively and irreversibly to Jak3. In a further embodiment, the kinase inhibitor binds selectively and irreversibly to Tec. In a further embodiment, the kinase inhibitor binds selectively and irreversibly to Btk and Tec. In a further embodiment, the kinase inhibitor binds Blk selectively and irreversibly. In a further embodiment, the kinase inhibitor binds reversibly and non-selectively to a plurality of src family protein kinase inhibitors. In a further embodiment, the kinase inhibitor has a plasma half-life of less than about 3 hours. In a further embodiment, the kinase inhibitor has a plasma half-life of less than about 2 hours.

In one embodiment is a kinase inhibitor that selectively and irreversibly binds to a protein tyrosine kinase selected from the group consisting of Btk, Btk homologs and Btk kinase cysteine homologs, wherein the kinase inhibitor is reversible and non-selective binds selectively to a number of protein tyrosine kinases, and further wherein the kinase inhibitor has a plasma half-life of greater than about 12 hours. In such an embodiment, the kinase inhibitor selectively and irreversibly binds to at least one of Btk, Jak3, Blk, Bmx, Tec, and Itk. In a further embodiment, the kinase inhibitor binds selectively and irreversibly to Btk. In a further embodiment, the kinase inhibitor binds selectively and irreversibly to Jak3. In a further embodiment, the kinase inhibitor binds selectively and irreversibly to Tec. In a further embodiment, the kinase inhibitor binds selectively and irreversibly to Btk and Tec. In a further embodiment, the kinase inhibitor binds Blk selectively and irreversibly. In a further embodiment, the kinase inhibitor binds reversibly and non-selectively to a plurality of src family protein kinase inhibitors. In a further embodiment, the kinase inhibitor has a plasma half-life of the kinase inhibitor greater than about 16 hours.

In another aspect of such methods of administration is a pharmaceutical formulation comprising any of the foregoing ACK inhibitors and a pharmaceutically acceptable excipient. In some embodiments, such pharmaceutical formulations are formulated for a route of administration selected from oral, parenteral, buccal, nasal, topical, or rectal administration. In certain embodiments, pharmaceutical formulations are formulated for oral administration.

In another aspect of such methods of administration is a method of treating rheumatoid arthritis comprising administering to a subject any of the aforementioned ACK inhibitors that selectively and irreversibly bind to Btk and Tec.

In a further aspect of such dosing strategies are methods of treating a B-cell proliferative disorder or a mastocytoid proliferative disorder comprising administering to a patient in need thereof a pharmaceutical composition of any of the foregoing ACK inhibitors.

In a further aspect of such dosing strategies are methods of treating rheumatoid arthritis or a condition comprising administering to a patient in need thereof a pharmaceutical composition of any of the foregoing ACK inhibitors. In a further aspect of such dosing strategies are methods of treating diseases characterized by hyperactive B cells comprising administering to a patient in need thereof a pharmaceutical composition of any of the foregoing ACK inhibitors. In a further aspect of such dosing strategies are methods of treating diseases characterized by hyperactive mast cells comprising administering to a patient in need thereof a pharmaceutical composition of any of the foregoing ACK inhibitors. In a further aspect of such dosing strategies are methods of treating diseases characterized by hyperactive B cells and hyperactive mast cells comprising administering to a patient in need thereof a pharmaceutical composition of any of the foregoing ACK inhibitors. In any of the foregoing methods of treatment using such dosing strategies, the pharmaceutical composition is administered once a day or less frequently than once a day.

Kit/Product

Also described herein are kits and articles of manufacture for use in the therapeutic applications described herein. Such kits may include a carrier, pack, or container divided to receive one or more containers, eg, vials, tubes, etc., each container containing a separate element for use in the methods described herein. Suitable containers include, for example, bottles, vials, syringes and test tubes. Containers can be constructed from a variety of materials such as glass or plastic.

The articles of manufacture provided herein include packaging materials. Packaging materials for use in packaging pharmaceutical products include, for example, US Patent Nos. 5,323,907, 5,052,558, and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for the selected formulation and intended mode of administration and treatment. A number of formulations of the compounds and compositions provided herein are contemplated as a variety of treatments for any disease, disorder or condition that would benefit from inhibition of Btk or in which Btk is a mediator or contributor to symptoms or causes.

For example, a container can include one or more compounds described herein, optionally in a composition or in combination with another agent, as disclosed herein. The container optionally has a sterile access port (eg, the container can be a bag for an intravenous solution or a vial with a stopper pierceable by a hypodermic needle). Such kits optionally comprise the compound, together with an identifying description or label or instructions relating to its use in the methods described herein.

Kits will typically include one or more additional containers, each containing one or more of the various materials (e.g., reagents, optionally in concentrated form, and and/or device). Non-limiting examples of such materials include, but are not limited to, buffers, diluents, filters, needles, syringes; carriers, packs, containers, vials, and/or tube labels - which list the contents and/or instructions for use, and a package insert with instructions for use. A set of instructions will also typically be included.

A label can be on or associated with a container. A label may be on a container when the letters, numbers, or other characters forming the label are attached, molded, or inscribed on the container itself; Can be associated with a container. A label may be used to indicate the specific therapeutic application for which the contents are intended. The label can also indicate directions for use of the contents, eg, for use in the methods described herein.

In certain embodiments, pharmaceutical compositions can be presented in a pack or dispenser device, which can contain one or more unit dosage forms comprising a compound provided herein. The pack may eg comprise metal foil or plastic film, eg a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied by a notice associated with the container in a form prescribed by a governmental agency regulating the manufacture, use, or sale of drugs, which notice reflects that the drug form is approved by that agency for human or veterinary administration. Such notifications could be, for example, the labeling of a prescription drug approved by the Food and Drug Administration, or an approved product insert. Compositions comprising a compound provided herein formulated in a compatible pharmaceutical carrier can also be prepared, placed in an appropriate container, and labeled for treatment of the indicated condition.

Example

The following specific non-limiting examples are to be construed as merely illustrative and not restrictive of the present disclosure in any way. While further elaboration is not required, it is believed that one skilled in the art can, based on the description herein, fully utilize the present disclosure.

compound synthesis

Synthetic Scheme I

step 1:

m-Phenylenediamine (0.500g, 4.62mmol), (Boc) ₂ O (0.92mL, 4.02mmol) and triethylamine (1.4mL, 9.98mmol) were added to 1,4-dioxane In a mixed solvent system of ring and water (30 mL, 2:1 V/V). After the reaction system was stirred at 0° C. for 1 hour, it was returned to room temperature and stirred for 10 hours. The reaction solution was concentrated under reduced pressure to obtain a yellow oil, which was dissolved in ethyl acetate and washed successively with saturated sodium bicarbonate solution and saturated brine. Finally, the organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (n-hexane _: ethyl acetate=10:1~8:1~4:1~2:1~1:1) to obtain compound 2 (0.48g, yield: 58%) It is a white solid.

Step 2:

Compound 2 (0.352g, 1.69mmol) and 2-chloro-5-nitropyrimidine (0.270g, 1.69mmol) were first dissolved in 12mL of acetonitrile. Potassium carbonate (0.702 g, 5.08 mmol) was then added to the solution. After the entire reaction system was stirred at room temperature for 3 hours, the reaction solvent was removed by rotary evaporation under reduced pressure, and the concentrate was dissolved in ethyl acetate and washed with water and saturated brine in sequence. The final organic phase was dried over sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1~3:1~2:1~1:1~1:3) to obtain the product 3 (0.50 g, yield: 89%) as a yellow solid.

Step 3:

Compound 3 (0.500 g, 1.51 mmol) and palladium carbon (0.16 g mass fraction: 5%) were added to a 25 ml two-neck flask, and 10 ml of methanol was added to the reaction system while maintaining slow stirring. After the air in the entire reaction system was replaced by nitrogen, a hydrogen balloon filled with sufficient hydrogen was connected to the system, and then the nitrogen in the reaction system was replaced by hydrogen in the balloon (three times). The reaction system was kept stirring at room temperature for 3 hours and then the reaction was terminated. The reaction solution was filtered with a sand core funnel to remove residual palladium carbon to obtain a brown filtrate. After the filtrate was concentrated, it was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1~1:2~1:4~1:6) to obtain product 4 (0.45g, yield: 100%) as a yellow solid .

Step 4:

3-Trifluoromethylbenzoic acid (0.500 g, 2.63 mmol) was dispersed in 5 mL of thionyl chloride, and the reaction system was heated to 80° C., kept stirring and refluxed for 1 hour, and then cooled to room temperature. After adding 10 ml of toluene to the reaction solution while maintaining slow stirring, it was concentrated by rotary evaporation under reduced pressure to a light yellow oily substance. After the concentrate was dissolved in 15ml of dichloromethane, 5-amino-2-methylbenzoic acid (0.478g, 3.16mmol) and diisopropylethylamine (0.1mL) were added to the solution, and the reaction system was After stirring overnight, a large amount of white solid precipitated out. The reaction solution was concentrated under reduced pressure, dispersed in ethyl acetate, washed with saturated ammonium chloride solution and saturated brine successively, and finally the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain the product 5 (0.68 g, Yield: 80%) as a white solid.

Step 5:

Compound 4 (0.263 g, 0.813 mmol) was dispersed in 3 mL of thionyl chloride, and the reaction system was heated to 80° C., stirred and refluxed for 1 hour, and then returned to room temperature. 5ml of toluene was added to the reaction solution under slow stirring, and the reaction solution was concentrated under reduced pressure to obtain a brown oil. After the concentrate was dissolved in 5mL of dichloromethane, compound 5 (0.270g, 0.894mmol) and diisopropylethylamine were added (0.1 mL). The final reaction system was stirred at room temperature overnight, and the reaction solution was concentrated to a solid under reduced pressure. The residue was dissolved in ethyl acetate and washed successively with saturated sodium bicarbonate solution and saturated brine. The final organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1～1:1～1:2～1:4) to obtain compound 6 ( 0.451 g, yield: 92%) as a yellow solid.

Step 6:

Compound 6 (0.278g, 0.458mmol) was dispersed in 2mL of dichloromethane, and 2mL of trifluoroacetic acid was slowly dropped into the reaction system under stirring. After the final reaction system was kept stirring at room temperature for 1 hour, it was concentrated under reduced pressure to obtain a solid. The residue was dissolved in ethyl acetate and washed successively with 10% sodium hydroxide solution and saturated brine. The final organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1～1:2～1:4) to obtain product 7 (0.193g, produced Yield: 83%) as a white solid.

Synthetic Scheme II:

step 1:

Compound 7 (0.080 g, 0.16 mmol) was dispersed in a mixed solvent of THF and water (4 mL, 1:1 V/V), and then diisopropylethylamine (27 μL, 0.16 mmol) was added. While maintaining slow stirring, acryloyl chloride (13 μL, 0.16 mmol) was slowly dropped into the reaction system. After the reaction solution was stirred at room temperature for 2 hours, it was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate and washed successively with 10% citric acid solution and saturated brine. The final organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1～1:2) to obtain product 8 (80mg, yield: 89%) It is a white powdery solid.

Synthetic Scheme III

step 1:

Glycine (1.00 g, 13.3 mmol) was dissolved in a mixed solvent of potassium hydroxide aqueous solution and 1,4-dioxane (40 mL, 1:1 V/V). (Boc) _2O (3.7 mL, 16.0 mmol) was added to the reaction solution. After the reaction system was stirred at room temperature for 12 hours, the reaction solution was concentrated under reduced pressure, and the concentrate was dissolved in ethyl acetate, and washed successively with 10% sodium bisulfate solution and saturated brine. The final organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude product 9 (2.33 g, yield: 100%) as an off-white solid.

Step 2:

Compound 7 (0.090g, 0.177mmol), Boc-protected glycine 9 (0.032g, 0.213mmol) and HATU (0.101g, 0.266mmol) were dissolved in 3mL DMF, and diisopropylethylamine was added under slow stirring ( 44 μL, 0.266 mmol). After the reaction solution was kept stirring at room temperature for 2 hours, the solvent was removed by rotary evaporation under reduced pressure, and the residue was dissolved in ethyl acetate, and then washed successively with saturated sodium bicarbonate solution and saturated brine. The final organic phase was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1～1:2～1:4) to obtain product 10 (0.106g , Yield: 90%) as a white solid.

Step 3:

Compound 10 (0.102 g, 0.154 mmol) was dispersed in 2 mL of dichloromethane, and 2 mL of trifluoroacetic acid was slowly dropped into the reaction system while maintaining stirring. After the final reaction system was kept stirring at room temperature for 1 hour, it was concentrated under reduced pressure to obtain a solid. The residue was dissolved in ethyl acetate and washed successively with 10% sodium hydroxide solution and saturated brine. The final organic phase was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and dried in vacuo overnight to obtain product 11 (0.080 g, yield: 92%) as a white solid.

Step 4:

Compound 11 (0.050 g, 0.089 mmol) was dispersed in a mixed solvent of THF and water (2 mL, 1:1 V/V), and then diisopropylethylamine (18 μL, 0.11 mmol) was added. While maintaining slow stirring, acryloyl chloride (14 μL, 0.18 mmol) was slowly dropped into the reaction system. After the reaction solution was stirred at room temperature for 2 hours, it was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed successively with saturated sodium bicarbonate solution and saturated brine. The final organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:2～1:4～1:8～100% EA) to obtain the product 12 ( 43 mg, yield: 79%) as a white solid.

In vitro inhibitory activity analysis of Btk

In a cell-free kinase assay, the _BtkIC50 of the compounds of the invention can be determined by the method described below or by an analogous method.

Btk kinase activity was determined using the time-resolved fluorescence resonance energy transfer (TR-FRET) method. Assays were performed in 50 μL reaction volumes using 96-well assay plates. Kinase, inhibitor, ATP (at the K _m of the kinase) and 1 μM peptide substrate (biotin-AVLESEEELYSSARQ-NH ₂ ) were incubated for 1 hour in reaction buffer (pH 7.4) consisting of 20 mM Tris , 50 mM NaCl, MgCl ₂ (5-25 mM, depending on the kinase), MnCl ₂ (0-10 mM), 1 mM DTT, 0.1 mM EDTA, 0.01% bovine serum albumin, 0.005% Tween-20 and 10% DMSO. The reaction was quenched by adding 25 [mu]L of 1.2 equivalents of EDTA (relative to the divalent cation) in 1x Lance buffer (Perkin-Elmer). Streptavidin-APC (Perkin-Elmer) and Eu-labeled p-Tyr100 antibody (Perkin-Elmer) in 1x Lance buffer were added in a volume of 25 μL to obtain final concentrations of 100 nM and 2.5 nM, respectively, and the mixture was incubated. Incubate for 1 hour. TR-FRET signals were measured using a multimode plate reader at an excitation wavelength (λ _Ex ) of 330 nm and detection wavelengths (λ _Em ) of 615 nm and 665 nm. Activity was determined by the ratio of fluorescence at 665 nm to 615 nm. For each compound, the enzyme activity at different concentrations of the compound was determined. Negative control reactions were performed in the absence of inhibitor (six duplicates), and two no-enzyme controls were used to determine baseline fluorescence levels. IC50 was obtained by fitting using the program Batch Ki ( _Kuzmic et al. (2000), Anal. Biochem. 286: _45-50 ).

Example compounds 1-37 of the present invention were synthesized according to the above synthesis schemes I, II and III. The specific synthesis steps and the characterization of the example compounds are shown in the table below. In the in vitro inhibitory activity analysis of Btk, the IC ₅₀ value of the embodiment compound 1-37 of the present invention was determined, and in the table below, the IC ₅₀ value is given according to the interval of the IC ₅₀ value, wherein "+++" represents IC ₅₀ <100nM;"++" means 100nM<IC ₅₀ <1000nM;"+" means 1000nM<IC ₅₀ <10000nM.

Synthesis and Btk IC _immediate value of the embodiment compound of table 1

Inhibits phosphorylation of Tyr551 residue of Btk

In each well of a 12-well plate, 500,000 Ramos cells were cultured overnight in 1 ml of RPMI-1640 and 10% FBS medium. Compound 1 at different concentrations was added, and after incubation for 1 hour, antibodies against human IgM (final concentration 80 ng/ml) were added and incubated for 3-5 minutes. After centrifugation, cells were lysed by boiling in 50 μl of SDS buffer. The degree of phosphorylation of the Tyr residue at position 551 of Btk kinase was analyzed by Western blotting. The experimental results (see Figures 1 and 2) indicated that the compound 1 inhibited Y551 phosphorylation with an IC ₅₀ value of 36 nM.

Preparation of pharmaceutical composition (dosage form)

For illustrative purposes, the compositions described below are introduced as containing a compound described herein; any compound described herein is optionally used in such pharmaceutical compositions.

parenteral compositions

To prepare a parenteral pharmaceutical composition suitable for administration by injection, 100 mg of the water-soluble salt of the compound prepared in the Examples was dissolved in DMSO, and then mixed with 10 mL of 0.9% sterile saline. The mixture is incorporated into dosage unit forms suitable for administration by injection.

oral composition

To prepare a pharmaceutical composition for oral delivery, 100 mg of the compound prepared in the examples was mixed with 750 mg of starch. The mixture is incorporated into oral dosage units suitable for oral administration, such as hard gelatin capsules.

Sublingual (Hard Lozenge) Compositions

To prepare a pharmaceutical composition for oral delivery, such as hard lozenges, 100 mg of the compound prepared in the examples is mixed with 420 mg of powdered sugar mixed with 1.6 mL of light corn syrup, 2.4 mL of distilled water and 0.42 mL of peppermint extract. The mixture is gently blended and poured into molds to form lozenges suitable for buccal administration.

inhalation composition

To prepare a pharmaceutical composition for inhalation delivery, 20 mg of the compound prepared in the examples was mixed with 50 mg of anhydrous citric acid and 100 mL of 0.9% sodium chloride solution. The mixture is incorporated into an inhalation delivery unit suitable for inhalation administration, eg a nebulizer.

rectal gel composition

To prepare a pharmaceutical composition for rectal delivery, 100 mg of the compound prepared in the examples was mixed with 2.5 g of methylcellulose (1500 mPa), 100 mg of methylparaben, 5 g of glycerin and 100 mL of purified water. The resulting gel mixture is then incorporated into rectal delivery units, such as syringes, suitable for rectal administration.

topical gel composition

To prepare a topical gel pharmaceutical composition, 100 mg of the compound prepared in the examples was mixed with 1.75 g of hydroxypropylcellulose, 10 mL of propylene glycol, 10 mL of isopropyl myristate and 100 mL of purified alcohol USP. The resulting gel mixture is then incorporated into containers, such as tubes, suitable for topical application.

Ophthalmic Solution Compositions

To prepare an ophthalmic solution pharmaceutical composition, 100 mg of the compound prepared in Examples was mixed with 0.9 g of NaCl in 100 mL of purified water, and filtered using a 0.2 micron filter. The resulting isotonic solution is then incorporated into ophthalmic delivery units, such as eye drop containers, suitable for ophthalmic administration.

It can be understood that the examples and implementations described herein are only for the purpose of illustration, and that various modifications or changes made therefrom can enlighten those skilled in the art, and include the spirit and implementation of the application herein. scope and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

Claims (32)

1. A method for inhibiting kinases for non-therapeutic purposes, said method comprising making a compound of formula (I) or a pharmaceutically acceptable salt thereof and the Cys 481 residue of Btk or another homologous tyrosine kinase The cysteine residues at the corresponding positions form a covalent bond, Compounds of formula (I): in, W is selected from H, C _1-6 alkyl, -(NH-CO) _n -LL ₃ , -(CO-NH) _n -LL ₃ , and -(NH-CO) _n -NH-LL ₃ , in L is a bond, C _1-3 alkylene, or C _2-3 alkenylene, L ₃ is C _3-8 cycloalkyl, aryl optionally substituted by 1, 2 or 3 substituents selected from the group consisting of, Or heteroaryl: halogen, amino, C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkyl, n is an integer 0 or 1, in, The aryl is selected from phenyl, naphthyl, phenanthrenyl, anthracenyl, fluorenyl and indenyl; The heteroaryl is selected from the following groups: X is selected from H, halogen, and C _1-6 alkyl, R ₁ and R ₂ are independently of each other, identically or differently, selected from H, C(O) and S(O) ₂ ; L and L are independently _of each other, identically or differently, selected from C _{2-3 alkenyl} optionally substituted by C _1-3 alkyl, and C _1-3 alkyl-NHC(O)-C _2-3 alkenyl; The premise is that when R ₁ is H, L ₁ is absent, and when R ₂ is H, L ₂ is absent. 2. A method of inhibiting kinases for non-therapeutic purposes, said method comprising making a compound of formula (I) or a pharmaceutically acceptable salt thereof form a covalent bond with an amino acid residue of Btk: Compounds of formula (I): in, W is selected from H, C _1-6 alkyl, -(NH-CO) _n -LL ₃ , -(CO-NH) _n -LL ₃ , and -(NH-CO) _n -NH-LL ₃ , in L is a bond, C _1-3 alkylene, or C _2-3 alkenylene, L ₃ is C _3-8 cycloalkyl, aryl optionally substituted by 1, 2 or 3 substituents selected from the group consisting of, Or heteroaryl: halogen, amino, C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkyl, n is an integer 0 or 1, in, The aryl is selected from phenyl, naphthyl, phenanthrenyl, anthracenyl, fluorenyl and indenyl; The heteroaryl is selected from the following groups: X is selected from H, halogen, and C _1-6 alkyl, R ₁ and R ₂ are independently of each other, identically or differently, selected from H, C(O) and S(O) ₂ ; L and L are independently _of each other, identically or differently, selected from C _{2-3 alkenyl} optionally substituted by C _1-3 alkyl, and C _1-3 alkyl-NHC(O)-C _2-3 alkenyl; The premise is that when R ₁ is H, L ₁ is absent, and when R ₂ is H, L ₂ is absent. 3. A method for irreversibly inhibiting Btk kinase for non-therapeutic purposes, said method comprising combining a compound of formula (I) or a pharmaceutically acceptable salt thereof with Btk kinase: Compounds of formula (I): in, W is selected from H, C _1-6 alkyl, -(NH-CO) _n -LL ₃ , -(CO-NH) _n -LL ₃ , and -(NH-CO) _n -NH-LL ₃ , in L is a bond, C _1-3 alkylene, or C _2-3 alkenylene, L ₃ is C _3-8 cycloalkyl, aryl optionally substituted by 1, 2 or 3 substituents selected from the group consisting of, Or heteroaryl: halogen, amino, C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkyl, n is an integer 0 or 1, in, The aryl is selected from phenyl, naphthyl, phenanthrenyl, anthracenyl, fluorenyl and indenyl; The heteroaryl is selected from the following groups: X is selected from H, halogen, and C _1-6 alkyl, R ₁ and R ₂ are independently of each other, identically or differently, selected from H, C(O) and S(O) ₂ ; L and L are independently _of each other, identically or differently, selected from C _{2-3 alkenyl} optionally substituted by C _1-3 alkyl, and C _1-3 alkyl-NHC(O)-C _2-3 alkenyl; The premise is that when R ₁ is H, L ₁ is absent, and when R ₂ is H, L ₂ is absent. 4. A method for inhibiting kinases for non-therapeutic purposes, wherein said method comprises combining a compound of formula (I) or a pharmaceutically acceptable salt thereof with kinases, and the catalytic domain of the kinases adopts the conformation of an inactive state: Compounds of formula (I): in, W is selected from H, C _1-6 alkyl, -(NH-CO) _n -LL ₃ , -(CO-NH) _n -LL ₃ , and -(NH-CO) _n -NH-LL ₃ , in L is a bond, C _1-3 alkylene, or C _2-3 alkenylene, L ₃ is C _3-8 cycloalkyl, aryl optionally substituted by 1, 2 or 3 substituents selected from the group consisting of, Or heteroaryl: halogen, amino, C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkyl, n is an integer 0 or 1, in, The aryl is selected from phenyl, naphthyl, phenanthrenyl, anthracenyl, fluorenyl and indenyl; The heteroaryl is selected from the following groups: X is selected from H, halogen, and C _1-6 alkyl, R ₁ and R ₂ are independently of each other, identically or differently, selected from H, C(O) and S(O) ₂ ; L and L are independently _of each other, identically or differently, selected from C _{2-3 alkenyl} optionally substituted by C _1-3 alkyl, and C _1-3 alkyl-NHC(O)-C _2-3 alkenyl; The premise is that when R ₁ is H, L ₁ is absent, and when R ₂ is H, L ₂ is absent. 5. A method for inhibiting kinases for non-therapeutic purposes, wherein said method comprises combining a compound of formula (I) or a pharmaceutically acceptable salt thereof with kinases, and the kinase catalytic domain adopts the DFG-out conformation: Compounds of formula (I): in, W is selected from H, C _1-6 alkyl, -(NH-CO) _n -LL ₃ , -(CO-NH) _n -LL ₃ , and -(NH-CO) _n -NH-LL ₃ , in L is a bond, C _1-3 alkylene, or C _2-3 alkenylene, L ₃ is C _3-8 cycloalkyl, aryl optionally substituted by 1, 2 or 3 substituents selected from the group consisting of, Or heteroaryl: halogen, amino, C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkyl, n is an integer 0 or 1, in, The aryl is selected from phenyl, naphthyl, phenanthrenyl, anthracenyl, fluorenyl and indenyl; The heteroaryl is selected from the following groups: X is selected from H, halogen, and C _1-6 alkyl, R ₁ and R ₂ are independently of each other, identically or differently, selected from H, C(O) and S(O) ₂ ; L and L are independently _of each other, identically or differently, selected from C _{2-3 alkenyl} optionally substituted by C _1-3 alkyl, and C _1-3 alkyl-NHC(O)-C _2-3 alkenyl; The premise is that when R ₁ is H, L ₁ is absent, and when R ₂ is H, L ₂ is absent. 6. A method for inhibiting Btk kinase for non-therapeutic purposes, wherein said method comprises combining a compound of formula (I) or a pharmaceutically acceptable salt thereof with kinase, wherein the compound inhibits Tyr551 and/or Tyr223 residues of Btk Phosphorylation of bases: Compounds of formula (I): in, W is selected from H, C _1-6 alkyl, -(NH-CO) _n -LL ₃ , -(CO-NH) _n -LL ₃ , and -(NH-CO) _n -NH-LL ₃ , in L is a bond, C _1-3 alkylene, or C _2-3 alkenylene, L ₃ is C _3-8 cycloalkyl, aryl optionally substituted by 1, 2 or 3 substituents selected from the group consisting of, Or heteroaryl: halogen, amino, C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkyl, n is an integer 0 or 1, in, The aryl is selected from phenyl, naphthyl, phenanthrenyl, anthracenyl, fluorenyl and indenyl; The heteroaryl is selected from the following groups: X is selected from H, halogen, and C _1-6 alkyl, R ₁ and R ₂ are independently of each other, identically or differently, selected from H, C(O) and S(O) ₂ ; L and L are independently _of each other, identically or differently, selected from C _{2-3 alkenyl} optionally substituted by C _1-3 alkyl, and C _1-3 alkyl-NHC(O)-C _2-3 alkenyl; The premise is that when R ₁ is H, L ₁ is absent, and when R ₂ is H, L ₂ is absent. 7. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, wherein the pharmaceutical composition is formulated for the selected Routes of administration from oral, parenteral, buccal, nasal, topical or rectal administration: Compounds of formula (I): in, W is selected from H, C _1-6 alkyl, -(NH-CO) _n -LL ₃ , -(CO-NH) _n -LL ₃ , and -(NH-CO) _n -NH-LL ₃ , in L is a bond, C _1-3 alkylene, or C _2-3 alkenylene, L ₃ is C _3-8 cycloalkyl, aryl optionally substituted by 1, 2 or 3 substituents selected from the group consisting of, Or heteroaryl: halogen, amino, C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkyl, n is an integer 0 or 1, in, The aryl is selected from phenyl, naphthyl, phenanthrenyl, anthracenyl, fluorenyl and indenyl; The heteroaryl is selected from the following groups: X is selected from H, halogen, and C _1-6 alkyl, R ₁ and R ₂ are independently of each other, identically or differently, selected from H, C(O) and S(O) ₂ ; L and L are independently _of each other, identically or differently, selected from C _{2-3 alkenyl} optionally substituted by C _1-3 alkyl, and C _1-3 alkyl-NHC(O)-C _2-3 alkenyl; The premise is that when R ₁ is H, L ₁ is absent, and when R ₂ is H, L ₂ is absent. 8. A compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical combination comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient Use of a substance for the manufacture of a medicament for the treatment or prevention of mastocytosis, osteoporosis or bone resorption disorders: Compounds of formula (I): in, W is selected from H, C _1-6 alkyl, -(NH-CO) _n -LL ₃ , -(CO-NH) _n -LL ₃ , and -(NH-CO) _n -NH-LL ₃ , in L is a bond, C _1-3 alkylene, or C _2-3 alkenylene, L ₃ is C _3-8 cycloalkyl, aryl optionally substituted by 1, 2 or 3 substituents selected from the group consisting of, Or heteroaryl: halogen, amino, C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkyl, n is an integer 0 or 1, in, The aryl is selected from phenyl, naphthyl, phenanthrenyl, anthracenyl, fluorenyl and indenyl; The heteroaryl is selected from the following groups: X is selected from H, halogen, and C _1-6 alkyl, R ₁ and R ₂ are independently of each other, identically or differently, selected from H, C(O) and S(O) ₂ ; L and L are independently _of each other, identically or differently, selected from C _{2-3 alkenyl} optionally substituted by C _1-3 alkyl, and C _1-3 alkyl-NHC(O)-C _2-3 alkenyl; The premise is that when R ₁ is H, L ₁ is absent, and when R ₂ is H, L ₂ is absent. 9. A compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical combination comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient The use of a substance, in combination with an antibody drug, in the preparation of a medicament for treating cancer: Compounds of formula (I): in, W is selected from H, C _1-6 alkyl, -(NH-CO) _n -LL ₃ , -(CO-NH) _n -LL ₃ , and -(NH-CO) _n -NH-LL ₃ , in L is a bond, C _1-3 alkylene, or C _2-3 alkenylene, L ₃ is C _3-8 cycloalkyl, aryl optionally substituted by 1, 2 or 3 substituents selected from the group consisting of, Or heteroaryl: halogen, amino, C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkyl, n is an integer 0 or 1, in, The aryl is selected from phenyl, naphthyl, phenanthrenyl, anthracenyl, fluorenyl and indenyl; The heteroaryl is selected from the following groups: X is selected from H, halogen, and C _1-6 alkyl, R ₁ and R ₂ are independently of each other, identically or differently, selected from H, C(O) and S(O) ₂ ; L and L are independently _of each other, identically or differently, selected from C _{2-3 alkenyl} optionally substituted by C _1-3 alkyl, and C _1-3 alkyl-NHC(O)-C _2-3 alkenyl; The premise is that when R ₁ is H, L ₁ is absent, and when R ₂ is H, L ₂ is absent. 10. A compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical combination comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient Combination with anti-CD20 or anti-CD68 in the preparation of medicines for treating cancer: Compounds of formula (I): in, W is selected from H, C _1-6 alkyl, -(NH-CO) _n -LL ₃ , -(CO-NH) _n -LL ₃ , and -(NH-CO) _n -NH-LL ₃ , in L is a bond, C _1-3 alkylene, or C _2-3 alkenylene, L ₃ is C _3-8 cycloalkyl, aryl optionally substituted by 1, 2 or 3 substituents selected from the group consisting of, Or heteroaryl: halogen, amino, C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkyl, n is an integer 0 or 1, in, The aryl is selected from phenyl, naphthyl, phenanthrenyl, anthracenyl, fluorenyl and indenyl; The heteroaryl is selected from the following groups: X is selected from H, halogen, and C _1-6 alkyl, R ₁ and R ₂ are independently of each other, identically or differently, selected from H, C(O) and S(O) ₂ ; L and L are independently _of each other, identically or differently, selected from C _{2-3 alkenyl} optionally substituted by C _1-3 alkyl, and C _1-3 alkyl-NHC(O)-C _2-3 alkenyl; The premise is that when R ₁ is H, L ₁ is absent, and when R ₂ is H, L ₂ is absent. 11. The method according to any one of claims 1-6, wherein in the compound of formula (I), W is selected from H, ethyl, -(NH-CO) _n -LL ₃ , -(CO-NH) _n -LL ₃ , and -(NH-CO) _n -NH-LL ₃ , in L is a bond or a vinylene group, _L is cyclopropyl, phenyl, naphthyl, isoxazolyl, or benzo[d] optionally substituted by 1 or ₂ substituents selected from F, Cl, amino, methoxy, and CF ][1,3]dioxolyl, n is an integer 1. 12. The method according to any one of claims 1-6, wherein in the compound of formula (I), X is selected from H, F, Cl, and methyl. 13. The method according to any one of claims 1-6, wherein in the compound of formula (I), R ₁ and R ₂ are independently of each other, identically or differently, selected from H, C(O) and S(O) ₂ ; L ₁ and L ₂ are independently of each other, identically or differently, selected from C _2-3 alkenyl, and methyl-NHC (O)-vinyl; The premise is that when R ₁ is H, L ₁ is absent, and when R ₂ is H, L ₂ is absent. 14. The method according to any one of claims 1-6, wherein in the compound of formula (I), W is selected from H, ethyl, -(NH-CO) _n -LL ₃ , -(CO-NH) _n -LL ₃ , and -(NH-CO) _n -NH-LL ₃ , in L is a bond or a vinylene group, _L is cyclopropyl, phenyl, naphthyl, isoxazolyl, or benzo[d] optionally substituted by 1 or ₂ substituents selected from F, Cl, amino, methoxy, and CF ][1,3]dioxolyl, n is an integer 1, X is selected from H, F, Cl, and methyl, R ₁ and R ₂ are independently of each other, identically or differently, selected from H, C(O) and S(O) ₂ ; L ₁ and L ₂ are independently of each other, identically or differently, selected from C _2-3 alkenyl, and methyl-NHC (O)-vinyl; The premise is that when R ₁ is H, L ₁ is absent, and when R ₂ is H, L ₂ is absent. 15. The composition according to claim 7, wherein in the compound of formula (I), W is selected from H, ethyl, -(NH-CO) _n -LL ₃ , -(CO-NH) _n -LL ₃ , and -(NH-CO) _n -NH-LL ₃ , wherein L is a bond or a vinylene group, _L is cyclopropyl, phenyl, naphthyl, isoxazolyl, or benzo[d] optionally substituted by 1 or ₂ substituents selected from F, Cl, amino, methoxy, and CF ][1,3]dioxolyl, n is an integer 1. 16. The composition according to claim 7, wherein in the compound of formula (I), X is selected from H, F, Cl, and methyl. 17. The composition according to claim 7, wherein in the compound of formula (I), R ₁ and R ₂ are independently of each other, identically or differently, selected from H, C(O) and S(O) ₂ ; L ₁ and L ₂ are independently of each other, identically or differently, selected from C _2-3 alkenyl, and methyl-NHC (O)-vinyl; The premise is that when R ₁ is H, L ₁ is absent, and when R ₂ is H, L ₂ is absent. 18. The composition according to claim 7, wherein in the compound of formula (I), W is selected from H, ethyl, -(NH-CO) _n -LL ₃ , -(CO-NH) _n -LL ₃ , and -(NH-CO) _n -NH-LL ₃ , in L is a bond or a vinylene group, _L is cyclopropyl, phenyl, naphthyl, isoxazolyl, or benzo[d] optionally substituted by 1 or ₂ substituents selected from F, Cl, amino, methoxy, and CF ][1,3]dioxolyl, n is an integer 1, X is selected from H, F, Cl, and methyl, R ₁ and R ₂ are independently of each other, identically or differently, selected from H, C(O) and S(O) ₂ ; L ₁ and L ₂ are independently of each other, identically or differently, selected from C _2-3 alkenyl, and methyl-NHC (O)-vinyl; The premise is that when R ₁ is H, L ₁ is absent, and when R ₂ is H, L ₂ is absent. 19. Use according to any one of claims 8-10, wherein in the compound of formula (I), W is selected from H, ethyl, -(NH-CO) _n -LL ₃ , -(CO-NH) _n -LL ₃ , and -(NH-CO) _n -NH-LL ₃ , in L is a bond or a vinylene group, _L is cyclopropyl, phenyl, naphthyl, isoxazolyl, or benzo[d] optionally substituted by 1 or ₂ substituents selected from F, Cl, amino, methoxy, and CF ][1,3]dioxolyl, n is an integer 1. 20. The use according to any one of claims 8-10, wherein in the compound of formula (I), X is selected from H, F, Cl, and methyl. 21. The use according to any one of claims 8-10, wherein in the compound of formula (I), R ₁ and R ₂ are independently of each other, identically or differently, selected from H, C(O) and S(O) ₂ ; L ₁ and L ₂ are independently of each other, identically or differently, selected from C _2-3 alkenyl, and methyl-NHC (O)-vinyl; The premise is that when R ₁ is H, L ₁ is absent, and when R ₂ is H, L ₂ is absent. 22. Use according to any one of claims 8-10, wherein in the compound of formula (I), W is selected from H, ethyl, -(NH-CO) _n -LL ₃ , -(CO-NH) _n -LL ₃ , and -(NH-CO) _n -NH-LL ₃ , in L is a bond or a vinylene group, _L is cyclopropyl, phenyl, naphthyl, isoxazolyl, or benzo[d] optionally substituted by 1 or ₂ substituents selected from F, Cl, amino, methoxy, and CF ][1,3]dioxolyl, n is an integer 1, X is selected from H, F, Cl, and methyl, R ₁ and R ₂ are independently of each other, identically or differently, selected from H, C(O) and S(O) ₂ ; L ₁ and L ₂ are independently of each other, identically or differently, selected from C _2-3 alkenyl, and methyl-NHC (O)-vinyl; The premise is that when R ₁ is H, L ₁ is absent, and when R ₂ is H, L ₂ is absent. 23. A method of inhibiting kinases for non-therapeutic purposes, said method comprising making the following specific compounds or pharmaceutically acceptable salts thereof correspond to Cys 481 residues of Btk or the homologous corresponding positions of another tyrosine kinase The cysteine residues form a covalent bond, Specific compounds are selected from: 24. A method of inhibiting kinases for non-therapeutic purposes, said method comprising forming a covalent bond with an amino acid residue of Btk from the following specific compound or a pharmaceutically acceptable salt thereof: Specific compounds are selected from: 25. A method of irreversibly inhibiting Btk kinase for non-therapeutic purposes, said method comprising combining the following specific compounds or pharmaceutically acceptable salts thereof with Btk kinase: Specific compounds are selected from: 26. A method of inhibiting a kinase for non-therapeutic purposes, wherein said method comprises binding the following specific compound or a pharmaceutically acceptable salt thereof to the kinase, and the catalytic domain of the kinase adopts an inactive conformation: Specific compounds are selected from: 27. A method of inhibiting a kinase for non-therapeutic purposes, wherein said method comprises binding the following specific compound or a pharmaceutically acceptable salt thereof to the kinase, and the catalytic domain of the kinase adopts the DFG-out conformation: Specific compounds are selected from: 28. A non-therapeutic method for inhibiting Btk kinase, wherein said method comprises binding the following specific compound or a pharmaceutically acceptable salt thereof to the kinase, wherein the compound inhibits Tyr551 and/or Tyr223 residues of Btk Phosphorylation: Specific compounds are selected from: 29. A pharmaceutical composition comprising a therapeutically effective amount of the following specific compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, wherein the pharmaceutical composition is formulated for oral administration Routes of Administration, Parenteral, Oral, Nasal, Topical or Rectal: Specific compounds are selected from: 30. The following specific compounds or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising therapeutically effective amounts of the following specific compounds or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients are used in the preparation Use in a medicament for the treatment or prevention of mastocytosis, osteoporosis or bone resorption disorders: Specific compounds are selected from: 31. The following specific compounds or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising therapeutically effective amounts of the following specific compounds or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients, and antibodies Pharmaceutically in combination, use in the preparation of a medicament for the treatment of cancer: Specific compounds are selected from: 32. The following specific compounds or pharmaceutically acceptable salts thereof, or a pharmaceutical composition comprising a therapeutically effective amount of the following specific compounds or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients, and anti - the use of CD20 or anti-CD68 in combination for the preparation of a medicament for the treatment of cancer: Specific compounds are selected from: